(Fused) benz (thio) amides

ABSTRACT

A novel (fused) benz(thio)amide of the general formula: ##STR1## or a non-toxic salt thereof, wherein R 4  represents: 
     (i) when B represents a closed ring, a group of the general formula: ##STR2## wherein U represents an oxygen atom or a sulfur atom; or (ii) when B represents a divalent group, a group of the general formula: ##STR3## wherein R 5 , R 6 , R 7 , R 8 , n, m, p and q are as defined in the specification, and exclusing certain compounds as defined in the specification, depending on whether A represents a single bond or a group. The compounds are useful for the prevention and/or treatment of diseases induced by leukotrienes, 5α-reductase, phospholipase and aldose reductase in mammals, especially human beings.

This is a continuation of application Ser. No. 08/159,463 filed Nov. 30, 1993, now abandoned, which is a divisional of application Ser. No. 07/800,253, filed Nov. 29, 1991, which is a continuation of application Ser. No. 07/516,892 filed Apr. 30, 1990 (now abandoned), which is a divisional of application Ser. No. 07/332,930 filed Apr. 4, 1989 (now U.S. Pat. No. 4,939,141), which is a divisional of application Ser. No. 07/207,994 filed Jun. 17, 1988 (now U.S. Pat. No. 4,847,275), which is a divisional of application Ser. No. 06/767/538 filed Aug. 20, 1985 (now U.S. Pat. No. 4,780,469).

SUMMARY

This invention is related to novel (fused) benz(thio)amides.

More particularly, this invention is related to novel (fused) benz(thio)amides having an antagonistic activity on leukotrienes (SRS) and an inhibitory activity on 5α-Reductase; processes for the preparation of them; and pharmaceutical agent containing them as active ingredient.

BACKGROUND

In the study of prostaglandins (abbreviated as PG hereafter), many important discoveries have been made continuously in recent years. And so it was found a large change in the direction of the research and development of PG. In the compounds which have been newly found or newly confirmed their structure in PG family, it can be said that PG endoperoxides, (i.e. PGG₂ and PGH₂), thromboxane A₂ (abbreviated as TXA₂ hereafter), prostacyclin (i.e. PGI₂) and leukotriene C₄, D₄ and E₄ (abbreviated as LTC₄, LTD₄ and LTE₄, respectively, hereafter) etc. have especially strong and unique biological activities.

All the compounds of PG family containing various PG previously known well in addition to the above compounds, are biosynthesized from the same mother compound, i.e. arachidonic acid in a living body and, therefore, the metabolic routes starting from arachidonic acid is called "Arachidonate cascade" as a whole. The detailed explanation of each route and the pharmacological character of each metabolite are described in Igaku No Ayumi, 114, 378 (1980), ibid, 114, 462 (1980), ibid, 114, 866 (1980), ibid, 114, 929 (1980), Gendai Iryo, 12, 909 (1980), ibid, 12, 1029 (1980), ibid, 12, 1065 (1980) and ibid, 12, 1105 (1980) etc.

The arachidonate cascade can be largely divided into two routes; one is the route that cyclooxygenase acts on arachidonic acid to convert, into various PGs, e.g. prostaglandin F₂ (abbreviated PGF₂ hereafter), prostaglandin E₂ (abbreviated PGE₂ hereafter), PGI₂, TXA₂, via PGG₂ and further PGH₂ and the other is the route that lipoxygenase acts on arachidonic acid to convert, in hydroxyeicosatetraenoic acid (abbreviated as HETE hereafter) or leukotrienes, via hydroperoxyeicosatetraenoic acid (abbreviated HPETE hereafter).

As the former route is well known, it is not described in the present specification in detail. See Prostaglandin (1978), edited by Makoto Katori et al., published by Kohdan-sha.

Concerning the latter route, it has been known that various compounds are produced according to the following scheme I. ##STR4##

Besides being metabolized through a well known route, i.e. the route via PG endoperoxides, arachidonic acid is also metabolized through another route by the action of lipoxygenase. That is to say, arachidonic acid is metabolized by the action of lipoxygenase, e.g. 5-lipoxygenase, 12-lipoxygenase and 15-lipoxygenase, to 5-HPETE, 12-HPETE and 15-HPETE, respectively.

These HPETE are converted into 5-HETE, 12-HETE and 15-HETE, respectively, by the action of peroxidase converting a hydroperoxy group into a hydroxy group. Furthermore, LTA₄ is also produced from 5-HPETE by dehydration. LTA₄ is converted into leukotriene B₄ (abbreviated as LTB₄ hereafter) or LTC₄ enzymatically. Further, LTC₄ is converted into LTD₄ by the action of γ-glutamyl transpeptidase.

Moreover, it was recently defined that LTD₄ is metabolized to LTE₄ (see Biochem. Biophys. Res. Commun., 91, 1266 (1979) and Prostaglandins, 19(5), 645 (1980)).

Besides, SRS is an abbreviation of Slow Reacting Substance and it was named by Feldberg et al. for the substance released when perfusing cobra venom through isolated lung or incubating cobra venom with vitellus. And it was reported that the substance constricted ilem isolated from guinea pig slowly and continually (see J. Physiol., 94,187 (1938)).

Moreover, Kellaway et al. showed the relation between SRS-A and allergic reaction from the fact that SRS-A is released when an antigen is sensitized to perfusing lung isolated from guinea pig (see Quant. J. Exp. Physiol., 30, 121 (1940)).

Brocklehurst reported that when the antigen is sensitized to a lung fragment isolated from a bronchial asthmatics whose specific antigen is defined, by an operation, histamine and SRS-A are released and strongly constrict bronchial muscle. Since such constriction can not be prevented by an antihistaminic agent, he suggested that SRS-A is an important bronchoconstrictor in an asthmatic paroxysm (see Progr. Allergy, 6, 539 (1962)).

Since then, many reports were published, for instance, SRS-A prepared from human lung slice constrict a tracheal spiral of normal human (see Int. Arch. Allergy Appl. Immunol., 38, 217 (1970)); when SRS-A prepared from rats is injected intravenously to guinea pig, significant increase of pulmonary resistance is observed (see J. Clin. Invest., 53, 1679 (1974)); in addition, a subcutaneous injection of SRS-A to guinea pig, rat and monkey enhances vascular permeability (see Advances in Immunology, 10, 105 (1969), J. Allergy Clin. Immunol., 621,371 (1978), Prostaglandins, 19(5), 779 (1980) etc. ) .

Generally, the substance released by immunological reaction is called SRS-A. On the other hand, the substance released by non-immunological reaction such as calcium ionophore is called SRS. However, the above two substances have many similarities to each other and, therefore, it is considered they would probably be the same substance.

Further, it was confirmed that SRS or SRS-A is a mixture of LTC₄ and LTD₄. So it can be understood that the pharmacological characters of these leukotrienes are the same as those of SRS or SRS-A (see Proc. Natl. Acad. Sci. USA, 76, 4275 (1979), Biochem. Biophys. Res. Commun., 91, 1266 (1979), Proc. Natl. Acad. Sci. USA, 77, 2014 (1980) and Nature, 285, 104 (1980)).

Based on results of these studies, various leukotrienes (the structures of LTC₄, LTD₄ and LTE₄, and further other leukotrienes which may be confirmed in the future) biosynthesized from arachidonic acid via LTA₄, are considered to be important factors relating to the appearance of allergic tracheal and bronchial diseases, allergic lung diseases, allergic shock and various allergic inflammations.

To suppress leukotrienes is useful for the prevention and/or treatment of tracheal bronchial or lung diseases such as asthma, allergic lung diseases, allergic shock or various allergic diseases.

On the other hand, arachidonic acid is released from phospholipids by the action of phospholipase, and two routes were generally accepted that (1) one is the route that phospholipase A₂ is reacted on phosphatidyl choline, and (2) the other is the route that phospholipase C was reacted on phosphatidyl inositol to produce 1,2-diglyceride, and diglyceridelipase followed by monoglyceridelipase were reacted on it to release arachidonic acid (see Kagaku to Seibutsu (Chemistry and Biology), 21, 154 (1983)).

And it was known that arachidonic acid released is metabolized through two different routes i.e. (1) metabolizing route to bioactive substances e.g. prostaglandins (PGs), thromboxane A₂ (TXA₂) by cyclooxygenase, and (2) metabolizing route to bioactive substances e.g. SRS-A (Slow Reacting Substances of Anaphylaxis), hydroxyeicosatetraenoic acid (HETE) and leukotriene B₄ (LTB₄) by lipoxygenase (see Kagaku to Seibutsu (Chemistry and Biology), 21, 154 (1983)).

These metabolites are known as chemical mediators; for example, TXA₂ is a compound which have a potent activity of platelet aggregation and aotra contraction, SRS-A is a chemical mediator on asthma, LTB₄ is a chemical mediator on various inflammations (e.g. gout), and PGs are also chemical mediators on various inflammations which enhance a vascular permeability and a pain, and have a vasodilative action, pyrogenetic action and chemotactic action (see Prostaglandin (1978), edited by Makoto Katori et al, published by Kohdan-sha).

Arachidonic acid is converted and metabolized to various chemical mediators which act important physiological part in living body. And it was known that ill-balances of those chemical mediators induce various disorders.

And as antagonist of SRS, the groups of the compounds of general formula: ##STR5## (wherein from R¹ to R⁵ and R⁷ each represent a hydrogen atom, a hydroxy group, an alkyl group of from 1 to 6 carbon atom(s), an alkoxy group of from 1 to 6 carbon atom(s), an amino group, an acyl group, an acylamino group of from 2 to 6 carbon atoms, an alkenyl group of from 2 to 6 carbon atoms, a halogen atom or a phenylalkoxy group in which alkoxy have from 1 to 6 carbon atom(s); X represents a hydrocarbyl group of from 1 to 10 carbon atom(s) being optionally substituted by hydroxy group(s); A represents an oxygen atom or is absent; Q represents an alkylene, alkenylene or alkynylene group of from 2 to 6 carbon atoms which may be branched; D represents a carboxy group, a 5-tetrazolyl group or carbamido-5-tetrazolyl group.) were described in patent publications by Fisons Co., Ltd. Japanese patent Application No. 55-1273841, European Patent Publication No. 17332 or U.S. Pat. No. 4,281,008).

And, the following compounds were described in the patent application by Kissei Pharmaceutical Co., Ltd, as anti-allergic agent, of the general formula: ##STR6## (wherein R¹ and R² each represent a hydrogen atom or an alkyl group with 1-4 carbon atoms; R³ and R⁴ each represent a hydrogen atom or may be combined together to form an additional chemical bond; X represents a hydroxyl group, a halogen atom, a straight or branched chain saturated or unsaturated alkyl group with 1-4 carbon atoms, a straight or branched chain saturated or unsaturated alkoxy group with 1-4 carbon atoms, an acyloxy group with 1-4 carbon atoms, or a cycloalkyl group with up to 6 carbon atoms; n is zero or an integer of 1-3 with the proviso that when n is 2 or 3; X's may be the same or different and that when two X's are commonly the alkyl or alkoxy group, both X's may be combined together to form a ring; and Y represents a straight or branched chain alkylene group or a straight or branched chain oxyalkylene group connected to the benzene nucleus through an oxygen atom.) as well as physiologically acceptable salts thereof. (see U.S. Pat. No. 4,026,896.)

And benzamides, i.e. compounds represented by the general formula (I) depicted hereafter, were described wherein the symbol B is opened and R⁴ is a group of the formula: --OCH₂ COOR, in prior patent applications by the present inventors (see Japanese Patent Application (Kokai) Patent Application Nos. 60-97946, 60-116657, 60-142941 and 60-146855.

DISCLOSURE OF THE INVENTION

The present inventors have synthesized novel compounds of the general formula (I) depicted hereafter, which have a structure characterized as a (thio)amido group being substituted on a fused benzene ring or benzene ring and have been found the compounds have potent antagonistic activity on leukotrienes (SRS), and then achieved the present invention.

And, the compounds of the present invention also inhibit phospholipase, so inhibit release of arachidonic acid from phospholipids, and therefore are useful for prevention and/or treatment of diseases induced by arachidonate metabolites e.g. TXA₂, PGs, leukotrienes in mammals including human beings, especially human beings.

Examples of the diseases to the subject are various allergic diseases induced by leukotrienes described above, thrombosis e.g. one induced by injury (damage) of cerebral or coronary, endothelium or intima and inflammations e.g. arthritis, rheumatism (see Junkan Kagaku (Cardiovascular Science) 3, 484 (1983) Yakkyoku (Pharmacy) 34, 167 (1983)).

It was found that the compounds of the present invention also have an inhibitory activity on 5α-reductase described below, besides the activity of leukotriene antagonist and phospholipase inhibitor described above.

5α-Reductase presents in endoplasmic reticulum and nucleic acid, and it converts testosterone which is taken into a target tissue, into active 5α-dihydrotestosterone. The activated 5α-dihydrotestosterone induces cell proliferaction by binding to an intracelluar receptor. Activation of this enzyme is considered to cause some diseases such as prostatic hypertrophy, resulting in pattern baldness and acne.

As a matter of course, the compounds of the present invention have no activity peculiar like hormones, and inhibit 5α-reductase, so suppress increasing of 5α-dihydrotestosterone, therefore suppress cell proliferaction, and therefore are useful for the prevention and/or treatment of prostatic hypertrophy, male pattern baldness and acne in mammals including human beings especially human beings.

Furthermore, it was found that the compounds of the present invention also have an inhibitory activity on aldose reductases.

An aldose reductase is an enzyme which reduces an aldose (e.g. glucose, galactose) into the corresponding polyol (e.g. sorbitol, galactitol) in human beings or other animals. The sorbitol and galactitol produced by the action of this enzyme are accumulated in the crystalline lenses, the peripheral nerves, the kidney, etc. of diabetics including galactosemiacs thus causing the above described complications e.g. retinopathy, diabetic cataract, nerve disturbances or renal disorders (see Jap. J. Opthamol., 20, 399 (1976), Int. Congr. Ser. Excepta Med., 403, 594 (1977) and Metabolism, 28, 456 (1979)).

The compounds of the present invention have inhibitory activity on an aldose reductase and are therefore effective for the prevention and/or treatment of diabetic complications described above in mammals including human beings especially human beings.

That is the present invention relates to that novel (fused) benz (thio) amides of the general formula: ##STR7## (wherein, A represents a single bond or a group of methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene group optionally being substituted by one, two or three of straight or branched alkyl group(s) of from 1 to 10 carbon atom(s) and/or phenyl group(s);

B represents

(i) a carbocyclic ring of from 4 to 8 members being unreplaced or replaced one, two or three of optional carbon atom(s) by oxygen, nitrogen and/or sulphur atom(s) (the ring may optionally be substituted by group(s) of oxo, thioxo and/or hydroxy group(s)) or

(ii) a divalent group of formula: ##STR8##

T represents an oxygen atom or a sulphur atom.

R¹ represents a group of general formula: ##STR9##

(iv) a straight or branched alkyl, alkenyl or alkynyl group of up to 20 carbon atom(s); (wherein R⁵ and R⁶ independently represent a hydrogen atom or a halogen atom or a straight or branched alkyl, alkenyl or alkynyl group of up to 20 carbon atom(s) unreplaced or replaced one, two,three, four or five of optional carbon atom(s) by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) and/or nitro group(s));

R² represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s);

R³ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a group of general formula: --COOR⁷ (wherein R⁷ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s)) or a straight or branched alkyl, alkoxy or alkylthio group of from 1 to 6 carbon atom(s);

R⁴ represents

(i) when B represents a closed ring, a group of general formula: ##STR10## (wherein U represents an oxygen atom or a sulphur atom;

R⁸ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s), n and m represent an integer of from 1 to 10, respectively, p and q represent zero or an integer of from 1 to 10, respectively) or

(ii) when symbol B do not represent a ring, a group of general formula: ##STR11## (wherein R⁸, p and q represent the same meaning as depicted hereinbefore, with the proviso that, when B represents a group of formula: ##STR12## p does not represent zero);

with the proviso that, following compounds are excluded, i.e. compounds of general formula: ##STR13## (wherein A' is a vinylene or ethylene group optionally being substituted by straight or branched alkyl group(s) of from 1 to 4 carbon atom(s),

R^(4') is the general formula:

    --(CH.sub.2).sub.n --COOR.sup.8

(wherein R⁸ and n are defined the same as hereinbefore) and R^(1') is

(i) a group of the general formula: ##STR14## (wherein R^(5') and R^(6') are hydrogen atom(s), hydroxy group(s), halogen atom(s), straight or branched alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy or acyloxy group(s) of up to 4 carbon atom(s) or cycloalkyl group(s) of from 3 to 6 carbon atom(s), independently) or

(ii) a group of the general formula: ##STR15## (wherein R^(5') and R^(6') are the same meaning as depicted hereinbefore)) and non-toxic salts thereof, and processes for their preparation, and pharmaceutical agents including them or it as active ingredient.

The compounds of the present invention may be largely divided into the following two groups in accordance with whether B which is a closed ring or not.

That is the present invention includes compounds of the general formula: ##STR16## (wherein A, B, R¹, R², R³, R⁴, T and U have the same meaning as described hereinbefore.)

Both of the compounds of the general formula (IA) and (IB) are novel compounds per se,

The compounds of the general formula (IA) are quite novel, in chemical structure, because they have a (thio)amido group as well as benzene ring(s) and/or chromone skelton as the essential group, compared with the compounds of Fisons of the general formula (A), described hereinbefore in the background.

The compounds of the general formula (IB) are also novel compounds and have been first found to have inhibitory activities on 5α-reductase, on lipoxygenase and on aldose reductase, besides antagonistic activity on leukotrienes.

In the general formula (I), examples of the groups represented by R⁵ and R⁶ are the following:

a hydrogen atom, a halogen atom

an alkyl group of from 1 to 20 carbon atom(s)

an alkenyl or alkynyl group of from 2 to 20 carbon atoms

an alkoxy or alkylthio group of from 1 to 19 carbon atom(s)

an alkenyloxy, alkenylthio, alkynyloxy or alkynylthio group of from 3 to 19 carbon atoms

an alkyl group of from 1 to 19 carbon atom(s) substituted by halogen atom(s) and/or hydroxy group(s)

an alkenyl or alkynyl group of from 2 to 19 carbon atoms substituted by halogen atom(s) and/or hydroxy group(s)

an alkoxy or alkylthio group of from 1 to 18 carbon atom(s) substituted by halogen atom(s) and/or hydroxy group(s)

an alkenyloxy, alkenylthio, alkynylthio or alkynyloxy group of from 3 to 18 carbon atoms substituted by halogen atom(s) and/or hydroxy group(s)

an alkyloxyalkyl, alkenyloxyalkyl or alkyloxyalkenyl group of up to 19 carbon atoms

a cycloalkyl, cycloalkyloxy or cycloalkylthio group of from 4 to 7 carbon atoms

a phenyl, phenoxy or phenylthio group

an alkyl group of from 1 to 19 carbon atom(s) which has carbocyclic ring(s) of from 4 to 7 carbon atoms, benzene ring(s), naphthalene ring(s) or thiophene ring(s) in the middle or at the terminal thereof

an alkoxy, alkylthio, alkenyloxy, alkenylthio, alkynyloxy or alkynylthio group of up to 18 carbon atom(s) which have carbocyclic ring(s) of from 4 to 7 carbon atoms, benzene ring(s), naphthalene ring(s) or thiophene ring(s) in the middle or at the terminal thereof

a phenylthioalkoxy or phenyloxyalkyloxy group wherein the alkyl moiety is a group from 1 to 17 carbon atom(s)

a carboxyalkyloxy or alkoxycarbonylalkyloxy group of up to 19 carbon atoms

an alkoxycarbonyloxyalkyloxy group of from 3 to 19 carbon atoms

an alkenylcarbonyloxy group of from 3 to 20 carbon atoms

an alkylcarbonyl group of from 2 to 20 carbon atoms

an azidoalkyl, nitroalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl group of to 19 carbon atom(s)

an azidoalkyloxy, nitroalkyloxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy group of from 1 to 18 carbon atom(s)

an alkenylcarbonylamino group of frcm 3 to 19 carbon atoms

an alkylamino group of from 1 to 19 carbon atom(s)

groups described above further substituted by halogen atom(s), hydroxy group(s), azido group(s), nitro group(s) and/or carboxy group(s)

Among the groups described above, preferable groups as R⁵ and R⁶ are the following groups:

a hydrogen atom

a halogen atom

a straight or branched alkyl group of from 1 to 20 carbon atom(s)

a straight or branched alkoxy group of from 1 to 19 carbon atom(s)

a straight or branched alkenyloxy group of from 3 to 19 carbon atoms

a straight or branched alkynyloxy group of from 3 to 19 carbon atoms

a straight or branched alkylthio group of from 1 to 19 carbon atom(s)

a straight or branched alkyl group of from 1 to 18 carbon atom(s) being substituted by halogen atom(s)

a straight or branched alkyloxyalkyl group of from 2 to 19 carbon atom(s)

a cycloalkyl, cycloalkylalkyl (wherein alkyl moiety is a group of from 1 to 8 carbon atom(s)) or cycloalkylalkyloxy (wherein alkyl moiety is a group of from 1 to 8 carbon atom(s)) group optionally substituted by straight or branched alkyl group(s) of from 1 to 8 carbon atom(s), hydroxy group(s), halogen atom(s) and/or nitro group(s)

a phenyl, phenylalkyl (wherein alkyl moiety is a group of from 1 to 8 carbon atom(s)), phenylalkyloxy (wherein alkyl moiety is a group of from 1 to 8 carbon atom(s)) or phenylalkenyloxy (wherein alkenyl moiety is a group of from 2 to 8 carbon atom(s)) group optionally substituted by straight or branched alkyl group(s) of from 1 to 8 carbon atom(s),hydroxy group(s), halogen atom(s) and/or nitro group(s)

a naphthyl, naphthylalkyl (wherein alkyl moiety is a group from 1 to 8 carbon atom(s)), naphthylalkoxy (wherein alkyl moiety is a group from 1 to 8 carbon atom(s)) or naphthylalkenyloxy (wherein alkenyl moiety is a group from 2 to 8 carbon atoms) group optionally substituted by straight or branched alkyl group(s), hydroxy group, halogen atom(s) and/or nitro group(s)

a straight or branched alkoxy, alkenyloxy or alkyloxyalkyloxy group of up to 18 carbon atom(s) substituted by carbonyl, carbonyloxy and/or hydroxy group(s)

a straight or branched alkoxy group of from 1 to 17 carbon atom(s) substituted by phenoxy or phenylthio group(s)

a straight or branched alkoxy group of from 1 to 18 carbon atom(s) substituted by thiophene ring(s)

a straight or branched alkyl, alkenyl, alkoxy or alkenyloxy group of from 1 to 18 carbon atom(s) substituted by azido or nitro group(s) or amino group(s) optionally substituted by an alkyl group of from 1 to 6 carbon atom(s) (including dialkylamino group(s))

a straight or branched alkyl, alkenyl, alkoxy or alkenyloxy group of from 1 to 18 carbon atom(s) replaced by two kinds groups which are carbonyl group(s) and amino group(s)

An alkyl group of from 1 to 20 carbon atom(s) in the present invention means a group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicocyl group and an isomeric group thereof.

And an alkenyl and alkynyl group of from 2 to 20 carbon atom(s) mean corresponding groups described above.

An alkyl group of from 1 to 6 carbon atom(s) in the present invention means a methyl, ethyl, propyl, butyl, pentyl, or hexyl group, or an isomeric group thereof.

A cycloalkyl group of from 4 to 7 carbon atoms in the present invention means a cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

A halogen atom in the present invention means a chlorine, bromine, iodine or fluorine atom.

In the present invention, when a certain carbon atom is replaced by another atom, a ring or a group, any carbon atom(s) can be replaced, so far as the replacement per se can be acceptable chemically or physically. For example, "an isobutyl group replaced by a benzene ring in the middle or at the terminal" means an isopropylphenyl, dimethylphenylmethyl or 2-phenylpropyl group. When a carbon atom is replaced, hydrogen atom(s) may be added or removed suitably. For example, "a pentyl group replaced by a nitrogen atom at the 2nd position" means N-propylaminomethyl group. ##STR17##

And examples of carbocyclic rings of from 4 to 8 members being unreplaced or replaced one, two or three of optional carbon atom by oxygen, nitrogen and/or sulphur atom(s) (the ring may optionally be substituted by group(s) of oxo, thioxo and/or hydroxy group(s)) represented by B in the general formula (I) are the followings: ##STR18## (The rings above described may optionally be substituted by hydroxy group(s).)

The carbocyclic rings depicted above may be saturated rings or unsaturated ones, or aromatic rings or non-aromatic ones.

Any rings depicted above are preferable. And, when the rings are fused with benzene rings, the following fused benzene rings are especially preferable, i.e. the rings of the general formula: ##STR19## are the following rings: ##STR20##

And compounds wherein B is a opened group of the formula: ##STR21## are also preferable.

Process for the Preparation (1)

The present invention includes not only the compounds per se, non-toxic salts thereof, use or method, but also process for the preparation.

According to the present invention, the compounds of the present invention of the general formula (I) may be prepared by reacting a compound of general formula:

    R.sup.1 --A--COOH                                          (II)

(wherein R¹ and A have the same meaning as described hereinbefore) or a corresponding dithioic acid and a compound of general formula: ##STR22## (wherein B, R², R³ and R⁴ have the same meaning as described hereinbefore) to form amide-bond, and further subjecting the product thereof to saponification and/or esterification, if desired.

Reactions to form amide-bond are well known, it may be carried out, for example;

(A) by the method with using mixed acid anhydride

(B) by the method with using acid halide

(C) by the method with using DCC (Dicyclohexylcarbodiomide)

Concrete description of the methods described above are as follows:

(A) method with using mixed acid anhydride may be carried out, for example; an acid of the general formula (II) is reacted with an acid halide (pivaloyl chloride, thionyl chloride, tosyl chloride, mesyl chloride, oxalyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, THF etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, picoline etc.), at from 0° C. to 40° C. to give a mixed acid anhydride. The obtained acid mixed anhydride and an amine of the general formula (III) are reacted in an inert organic solvent (described above), at from 0° C. to 40°C.

(B) method with using acid halide may be carried out, for example; an acid of the general formula (II) is reacted with an acid halide (described above) in an inert organic solvent (described above) or without solvents at from -20° C. to a refluxing temperature of the solvent used to give an acid halide. The obtained acid halide and an amine of the general formula (III) are reacted in an inert organic solvent (described above) in the presence or absence of tertiary amine (described above) at from 0° C. to 40° C.

(C) method with using DCC may be carried out, for example; an acid of the general formula (II) and an amine of the general formula (III) are reacted in an inert organic solvent (described above) or without solvents in the presence or absence of tertiary amine (described above) using with DCC at from 0° C. to 40° C.

Preferably, the reactions (A), (B) and (C) described above are carried out in an atmosphere of inert gas (argon, nitrogen, etc.) under anhydrous conditions.

Process for the Preparation (2)

Among the compounds of the present invention, compounds of the general formula: ##STR23## PG,30 (wherein R²⁰ represents methylene group or a single bond, and A, B, R¹, R², R³ and T have the same meaning as described hereinbefore.) may be prepared by reacting a compound of the general formula: ##STR24## (wherein A, B, R¹, R², R³ and T have the same meaning as described hereinbefore) with an azide.

Reactions to induce a 2-tetrazolyl group from a cyano group with an azide are known, it may be carried out, for example, under anhydrous condition, using with azide (sodium azide, lithium azide, potassium azide etc.), in the presence of weak acid (pyridium chloride, ammonium chloride, dimethylaniline hydrochloride etc.) in an inert organic solvent (dimethylformamide, N-methylpyrrolidone etc.) with heating.

Process for the Preparation (3)

Among the compounds of the present invention, compounds of the general formula: ##STR25## (wherein R⁵⁵ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s), and A, R¹, R³, R²⁰ and T have the same meaning as described hereinbefore) may be prepared by reacting a compound of general formula: ##STR26## (wherein R¹, R³ and T have the same meaning as described hereinbefore) and a compound of general formula: ##STR27## (wherein X¹⁰ and X²⁰ represent halogen atoms respectively, and R⁵⁰ represents a straight or branched alkyl group of from 1 to 6 carbon atom(s), and R²⁰ has the same meaning as described hereinbefore) and further, subjecting the product thereof to esterification and/or saponification, if desired.

Reactions to form a benzodioxane ring from catechol are known, and it may be carried out, for example, under anhydrous conditions, in the presence of a condensing agent (potassium carbonate, sodium carbonate etc.) in an inert organic solvent (acetone, methyl ethyl ketone, dioxane etc.), with heating.

Process for the preparation (4)

Among the compounds of the present invention, compounds of the general formula: ##STR28## (wherein R¹²¹ represents a group of general formula: --(CH₂)_(r) -- (wherein r represents zero or an integer of from 1 to 9). R¹⁴⁰ represents a group of general formula: --COOR⁸ (wherein R⁸ has the same meaning as described hereinbefore) or a group of formula: ##STR29## And A, R¹, R², R³, T and U have the same meaning as described hereinbefore) may be prepared by reacting a compound of general formula: ##STR30## (wherein A, R¹, R², R³, T and U have the same meaning as described hereinbefore) and a compound of general formula:

    X.sup.110 --CH.sub.2 --R.sup.121 --R.sup.140               (XXXXVI)

(wherein X¹¹⁰ represents a halogen atom, and R¹²¹ and R¹⁴⁰ have the same meaning as described hereinbefore) and further subjecting the product thereof to saponification and/or esterification, if desired.

Reactions of O-alkylation are known, and it may be carried out, for example, under anhydrous conditions, in the presence of a base (sodium hydride, potassium carbonate, sodium carbonate etc.), in a polar aprotic solvent (diethyl ether, tetrahydropyran, acetone etc.) at from 0° C. to 100° C.

Process for the Preparation (5)

Among the compounds of the present invention of the general formula (I), certain compounds may be prepared from the corresponding compounds of the present invention.

For example, it may be carried out in the following reaction formula and reaction scheme [A]. ##STR31## (in the above case, a reaction starting with a compound of formula (Ic) which substitutes a butadienylene and butenylene group, or a group substituted by an alkyl or phenyl group for the vinylene group may also be carried out similarly) ##STR32## (wherein the symbol represents whole group of the substituent R¹ and symbols therein are included in R¹ respectively. R¹ and groups in R¹ have the same meaning as described above in the following schemes. R³⁰ represents an alkyl, alkenyl or alkynyl group of up to 18 carbon atom(s).) ##STR33##

Each symbol in the scheme [A] represents the following meanings or as defined hereinbefore respectively. R⁴⁰, R⁴¹ an alkyl, alkenyl or alkynyl group of up to 18 carbon atom(s)

R⁴⁵ a hydrogen atom or an alkyl, alkenyl or alkynyl group of up to 18 carbon atom(s)

T¹⁰ an oxygen atom or a sulphur atom, or an imido group

M¹⁰ a lithium, potassium or sodium atom

X¹ a halogen atom

Processes for the Preparation of Intermediates

Intermediates described hereinbefore of the general formula (III), (IV), (V) and (XXXXV) may be prepared by the processes described in the following reaction schemes, respectively.

Each symbol in the schemes represent the following meanings or as described hereinbefore, respectively.

R²¹ a straight or branched alkyl group of from 1 to 6 carbon atom(s)

R⁵¹, R⁵², R⁵³, R⁵⁶ a straight or branched alkyl group of from 1 to 6 carbon atom(s)

R⁵⁴ a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s)

R⁷⁰, R⁷¹ a trifluoroacetyl group

X³⁰ , X⁴⁰, X⁵⁰ a halogen atom

R¹²², R¹⁸⁰ a straight or branched alkyl group of from 1 to 6 carbon atom(s)

R¹²⁵ a group of formula: --U--(CH₂)_(n) -- or --(CH₂)_(p) -- (wherein U, n and p have the same meaning as described hereinbefore)

R¹⁵⁰ a trifluoroacetyl group

X¹²⁰, X¹³⁰, X¹⁴⁰, X¹⁵⁰ a halogen atom

When B contains an imino group, it is preferable to protect by trifluoro group(s) etc., and to remove the protecting group(s) in a suitable step.

And compounds of the general formula (IIIj) may be prepared by the same procedure as the method to obtain compounds of general formula (IIIh) from compounds of general formula (IIIg). ##STR34##

Intermediates having a 1,4-dithianaphthalene skeleton also may be prepared using with a compound of general formula: ##STR35## (Wherein R³ has as the same meaning as described hereinbefore) which may be obtained by hydrolyzing a compound of general formula: ##STR36## (wherein R³ as the same meaning as described hereinbefore) instead of the compound of the general formula (XIII).

In the processes for the preparation of the compounds of the present invention, esterification and saponification may be carried out as follows.

Conversion of a certain acid into a corresponding ester (i.e. esterification) is a known reaction per se, and it may be carried out, for example;

(1) by the method using a diazoalkane

(2) by the method using an alkyl halide

(3) by the method using DMF-alkylacetal and

(4) by the method reacting with a corresponding alkanol

Concrete descriptions of the reactions above mentioned are as follows:

(1) the method using a diazoalkane may be carried out, for example, in an inert organic solvent (diethyl ether, ethyl acetate, methylene chloride, acetone, methanol, ethanol etc.) using with corresponding diazoalkane.

(2) the method using an alkyl halide may be carried out, for example, in an organic solvent (acetone, N,N-dimethylformamide, DMSO etc.), in the presence of a base (potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium oxide etc.) using with a corresponding alkyl halide.

(3) the method using DMF-dialkylacetal may be carried out, for example, in an inert organic solvent (benzene, toluene etc.) using with a corresponding DMF-dialkylacetal.

(4) the method reacting with a corresponding alkanol may be carried out, for example, in a corresponding alkanol, using an acid (hydrochloric acid, sulphuric acid, p-toluenesulphonic acid, hydrochloride gas etc.) or condensing agent (DCC, pivaloyl chloride, arylsulphonyl halide, alkylsulphonyl halide etc.).

Reactions mentioned above are carried out generally at from -10° C. to 100° C.; and they may be carried out with a further addition of inert organic solvent(s) (THF, methylene chloride etc.) not related to the reactions.

Conversion of a certain ester into corresponding acid (i.e. saponification) is a known reaction per se, and it may be carried out, for example;

(1) using with an aqueous solution of an alkali (potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate etc.) in a water-miscible organic solvent (THF, dioxane, ethanol, methanol etc.).

(2) using an alkali mentioned above, in an alkanol (methanol, ethanol etc.) in anhydrous condition.

The reactions above are carried out generally at from -10° C. to 100° C.

In each reaction in the present invention, products may be purified by conventional manner. For example, it may be carried out by distillation at atmospheric or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization. Purification may be carried out after each reaction, or after a series of reactions.

Starting Materials

Starting materials and reagents in the present invention are known compounds per se or may be prepared by known methods per se.

For example, acids of the general formula (II) may be prepared by the methods described in the specification of Japanese Patent Application Kokai Nos. 60-97946, 60-116657, 60-142941, 60-142936 or 60-146855.

A certain compound of the general formula (VIII) wherein R³ is a hydrogen atom is described in J. Med. Chem., 8, 446 (1965).

A certain compound of the general formula (XIII) wherein R³ is a hydrogen atom is described in J. Am. Chem. Soc., 75, 3277 (1953).

The compounds of the general formula (XV) may be prepared by the method described in J. Med. Chem., 20, 371 (1977).

A certain compound of the general formula (XXXI) wherein R³ is a hydrogen atom is described in J. Org. Chem., 42, 1925 (1977).

The compounds of the general formula (XXXXVIII) may be prepared from the compounds of the general formula (II).

Compounds of the general formula (XXXXVI), (XXXXVII) and (XXXXVIII) are known compounds per se, or may be prepared by known methods per se.

For example, compounds wherein B is a morpholine ring, compounds wherein B is 2,3,4,5-tetrahydrofuran, compounds wherein B is a hydroxypyridine ring, compounds wherein B is 3,4,5,6-tetrahydro-2H-pyran ring may be prepared by the methods described in J. O. Chem., 32, 4155 (1967), Chem. Abst. 98, 179352 q (1983), J. O. Chem., 32, 4155 (1967), and Chem. Abst., 8., 58747z, respectively or similar methods thereof.

Salts

The compounds of the present invention of the general formula (I) may form salts at the carboxy or tetrazolyl moiety.

By converting into salts, solubility of the compounds of the present invention in water can be increased, and therefore may be more readily administered as pharmaceuticals.

The compounds of the present invention may easily be converted into corresponding salts by the methods known per se, e.g. methods described hereafter.

The salts in the present invention are preferably non-toxic ones. The non-toxic salts mean salts of cations such that are relatively innocuous to living body (animals including human beings) tissues and that the effective pharmacological properties of the compounds of the general formula (I) are not impaired by side effect(s) resulting from the cations when used in an amount required for the prevention and/or treatment. And water-soluble salts are preferable.

Suitable salts include, for example, a salt of an alkali metal such as sodium, potassium, a salt of an alkaline metal such as calcium, magnesium, an ammonium salt and a pharmaceutically acceptable (non-toxic) amine salt.

Amines suitable for forming such salts with carboxylic acid or tetrazolyl group are well known and include, for example, those amines which are theoretically obtained by Substituting one or more of hydrogen atom(s) of ammonia by other group(s). These groups, which may be the same or different when one or more hydrogen atom(s) are substituted, are selected from, for example, alkyl group(s) of from 1 to 6 carbon atom(s) and hydroxyalkyl group(s) of from 1 to 3 carbon atom(s). Suitable non-toxic amine salts include salts of a tetraalkylammonium group, such as tetramethylammonium salt and salts of an organic amine, such as methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, lysine and alginine.

Salts can be obtained from the compounds of the present invention of the general formula (I), by methods known per se, for example, by reacting the compound of the general formula (I) and a suitable base such as a hydroxide or carbonate of an alkali metal or alkaline earth metal, ammonium hydroxide, ammonia or an organic amine in theoretical amounts in an appropriate solvent.

The salts can be isolated by freeze-drying the solution, or by filtration if the salts are sufficiently insoluble to the reaction solution, or if necessary, by removing part of the solvent followed by filtration.

Pharmaceutical Activities

The compounds of the present invention possess an antagonistic activity on leukotrienes, inhibitory activity on phospholipase, on 5α-reductase and on aldose reductase.

In a standard laboratory test, for example, the compounds of the present invention showed the pharmaceutical activity in the following tables.

The compounds of the present invention showed an antagonistic activity on LTD₄ in vitro (method is described hereafter), shown in the following tables.

                  TABLE I                                                          ______________________________________                                         Antagonistic activity of compounds of following                                general formula on LTD.sub.4                                                    ##STR37##                    (IA')                                            R                    IC.sub.50 (μM)                                         ______________________________________                                         alkyl                0.07-40                                                   alkoxy               0.009-0.9                                                 alkenyloxy           0.0005-1.4                                                alkynyloxy           0.0002-0.013                                              alkylthio             0.17-17.5                                                alkoxy substituted by halogen atom                                                                  0.0004-0.007                                              cycloalkylalkoxy     0.08-0.2                                                  (alkyl)phenylalkoxy  0.0004-0.7                                                naphthylalkyl        0.008                                                     ______________________________________                                    

                  TABLE II                                                         ______________________________________                                         Antagonistic activity of compounds of following                                general formula on LTD.sub.4                                                    ##STR38##                   (IA")                                             R                     IC.sub.50 (μM)                                        ______________________________________                                         alkyl                 0.1-16                                                   alkoxy                0.004-2.3                                                alkenyloxy            0.02-1.8                                                 alkynyloxy            0.4-0.5                                                  alkylthio             0.3-1.1                                                  alkoxy substituted by halogen atom                                                                   0.003-0.08                                               cycloalkyl            0.5                                                      cycloalkylalkoxy      0.09-1.5                                                 phenylalkoxy          0.009-0.7                                                ______________________________________                                    

                  TABLE III                                                        ______________________________________                                         Comparison of activity by alkylene chain change                                                            IC.sub.50                                          Formula                     (μM)                                            ______________________________________                                          ##STR39##                  2.6                                                 ##STR40##                  8.3                                                 ##STR41##                  0.66                                                ##STR42##                  0.074                                               ##STR43##                  15.5                                                ##STR44##                  20.0                                               ______________________________________                                    

As is obvious from the Tables I and II, compounds of 1,4-benzodioxane skeleton having any substituent R, represented by the general formula (IA') or (IA") among the compounds of the present invention (i.e. the case when B and R⁴ are fixed and R¹ and A are changed in the general formula (I).) have enough activity for pharmaceutical use.

From Table III, it is confirmed that if the alkylene moiety (corresponding to A in general formula (I)) is converted, compounds having sufficient pharmaceutical activity are obtained.

In the following tables, the comparision of activity by skeleton structure changes are shown.

                  TABLE IV                                                         ______________________________________                                         Comparison of activity by skeleton structure change (1)                                                     IC.sub.50                                         Formula                      (μM)                                           ______________________________________                                          ##STR45##                   0.37                                               ##STR46##                   0.03                                               ##STR47##                   0.69                                              ______________________________________                                    

                  TABLE V                                                          ______________________________________                                         Comparison of activity by skeleton structure change (1)                        Formula                    IC.sub.50 (μM)                                   ______________________________________                                          ##STR48##                 2.6                                                  ##STR49##                 0.18                                                 ##STR50##                 1.2                                                 ______________________________________                                    

                  TABLE VI                                                         ______________________________________                                         Comparison of activity by skeleton structure change (3)                        Example       Symbol                                                           No.           B          IC.sub.50 (μM)                                     ______________________________________                                         1(501)                                                                                        ##STR51## 0.076                                                 1(505)                                                                                        ##STR52## 0.205                                                 1(514)                                                                                        ##STR53## 0.0046                                                1(516)                                                                                        ##STR54## 0.0026                                                1(518)                                                                                        ##STR55## 0.033                                                 1(521)                                                                                        ##STR56## 0.0013                                                ______________________________________                                    

And further, from Tables IV, V and VI, it is clear that compounds in which the basic structural skeleton contains various rings also possess sufficient activity compared with the compounds having a 1,4-benzodioxane skeleton (i.e., when R¹ and A are fixed and B and R⁴ are changed).

According to the points above described, it is estimated fairly that replacement of an essential skeleton structure of a certain compound from 1,4-benzodioxan to various rings and/or change of the groups of general formula: R¹ --A-- in the general formula (I) also leads to a compound having enough activity for pharmaceutical use.

From these data, it is fully expected that the full scope of the present invention has effective activity and therefore is useful as a pharamaceutical agent.

Antagonistic activity of the compounds of the present invention on LTD₄ were measured by the following method.

A segment of ilem (2.5 cm) was removed from guinea pig 300-400 g and suspended in a Magnus tube containing Tyrodes solution. The tube was maintained at 37° C. and aerated with 95% 02 - 5% CO₂. After stabilizing from 30 mins, 5×10⁻⁹ g/ml of LTD₄ was added to the Magnus tube. Contraction length at the time and contraction lengths when the compounds of the present invention were challenged at some concentrations were measured, and the IC₅₀ value were calculated.

(2) Inhibitory activity on 5α-reductase in vitro

The compounds of the present invention showed an inhibitory activity on 50α-reductase in vitro (method is described hereafter), shown in the following table.

                  TABLE VII                                                        ______________________________________                                         Inhibitory activity on 5α-reductase                                             Example                                                                        No.    IC.sub.50 (μM)                                                ______________________________________                                                4(204) 2                                                                       4(206) 4                                                                       6(1)   5                                                                ______________________________________                                    

Inhibitory activity of the compounds of the present invention on 5α-reductase was measured by the following method.

Inhibitory activity of the compounds of the present invention on 5α-reductase (IC₅₀) in vitro was measured by the following method.

Compounds tested were incubated with radioactive [4-¹⁴ C]testosterone (5 μM) and NADPH (5×10⁻³ M) in the medium containing 5α-reductase, 0.09M Hepes (pH 7.4) and 0.22M sucrose at 37° C. for 60 mins. The reaction was stopped by adding solution of chloroform-methanol ( 1:2). The reaction mixture was centrifuged and the supernatant was separated by thin layer chromatography on silica gel using chloroform-methanol-acetic acid (99.2:0.6:0.2) as a developing solvent. Radioactivity of formed 5α-dihydrotestosterone was measured by TLC scanner. The values of IC₅₀ were measured by the inhibition percents of 5α-reductase activity measured by the above procedure (see Endocrinal, Japon. , 18,179 (1971).).

Toxicity

On the other hand, it was confirmed that the acute toxicity (LD₅₀) over the full scope of the present invention was more than 500 mg/kg animal body weight by intravenous administration. Therefore, the compounds of the present invention may be considered to be sufficiently safe and suitable for pharmaceutical use.

For example, the values of LD₅₀ of the compounds prepared in Examples 1(76), 1(212), 1(230) and 1(247) were more than 1000 mg/kg animal body weight by intravenous administration in male mice weighing 170-180 g, respectively.

Application for Pharmaceuticals

The present invention is also related to methods of use as a leukotriene antagonist, phospholipase inhibitor, 5α-reductase inhibitor and/or aldose reductase inhibitor.

Suppressing leukotrienes is useful for the prevention and/or treatment of tracheal bronchial or lung diseases such as asthma, allergic lung diseases, allergic shock or various allergic diseases in mammals including human beings, especially human beings.

Inhibiting phospholipases (phospholipase A₂ and/or phospholipase C) is useful for the prevention and/or treatment of diseases induced by the metabolites of arachidonic acid including leukotrienes described above, e.g. thrombosis such as thrombosis induced by damage of cerebral or coronary, endothelium or intina and inflammations such as arthritis, rheumatism in mammals including human beings, especially human beings.

Inhibiting 5α-reductase is useful for the prevention and/or treatment of prostatic hypertrophy, male pattern baldness or acne in mammals including human beings, especially human beings.

Inhibiting aldose reductases is useful for the prevention and/or treatment of diabetic complications e.g. retinopathy, diabetic cataract, nerve disturbances or renal disorders.

For the purposes hereinbefore described, the compounds of the present invention of the general formula or non-toxic salts thereof may normally be administered systemically or partially; usually by oral or parenteral administration.

The doses to be administered is determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 0.1 mg and 100 mg, preferably between 2 mg and 20 mg, by oral administration, up to several times per day, and between 10 ug and 10 mg, preferably between 0.1 mg and 1 mg, by parenteral administration up to several times per day.

As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.

Solid compositions according to the present invention for oral administration include compressed tablets, dispersible powders and granules. In such solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate aluminate. The compositions may also comprise, as is normal practice, additional substances other than inert diluents e.g. lubricating agents such as magnesium stearate, disintegrating agents such as cellulose calcium gluconate, and assistant for dissolving e.g. arginine, glutamic acid or amino-acid such as aspartic acid. The tablets or pills may, if desired, be made into gastric film-coated or enteric film-coated tablets or pills, such as sugar-coated, gelatin-coated, hydroxypropyl cellulose-coated or hydroxypropylmethyl cellulose phthalate-coated tablets or pills; two or more of layers may be used. The compositions for oral administration also include capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as distilled water or ethanol. Besides inert diluents such compositions may also comprise adjuvants such as wetting and suspending agents, and sweetening, flavoring, perfuming and preserving agents.

Other compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s).

Preparations for injection according to the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of aqueous solvents or suspending media are distilled water for injection and physiological salt solution. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, POLYSORBATE 80 (registered Trade Mark). These compositions may also include adjuvants such as preserving, wetting, emulsifying, despersing agents and assistant agent for dissolving (e.g. arginine, glutamic acid or amino-acid such as aspartic acid). They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Other compositions for parenteral administration include liquids for external use, and endermic liniments such as ointments, suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by known methods.

Nomenclature and excluding compounds

Throughout the specification including claims, the compounds of the present invention are named as derivatives having the following fused benzene rings or benzene ring.

    ______________________________________                                         1,4-benzodioxane                                                                                    ##STR57##                                                 4H-1-benzopyran                                                                                     ##STR58##                                                 2,3-dihydro-1,4-dithianaphthalene                                                                   ##STR59##                                                 benzofuran                                                                                          ##STR60##                                                 2,3-dihydro-1-benzofuran                                                                            ##STR61##                                                 quinoline                                                                                           ##STR62##                                                 1,3-benzodioxole                                                                                    ##STR63##                                                 naphthalene                                                                                         ##STR64##                                                 3,4-dihydro-2H-1,5-benzodioxepin                                                                    ##STR65##                                                 2,3-dihydro-1,4-benzoxazin                                                                          ##STR66##                                                 3,4-dihydro-2H-1-benzopyran                                                                         ##STR67##                                                 4H-1-benzothiopyran                                                                                 ##STR68##                                                 ______________________________________                                    

And throughout the specification including claims, isomers generated by the existence of stereo configuration unlimited (e.g. asymmetric carbon, double bond) are included in the corresponding formula, respectively.

However, compounds which do not normally exist for chemical or physical reasons according to general chemical knowledge are excluded from the present invention, e.g. certain compounds having a multiple bond adjacent to an oxygen, nitrogen or sulphur atom.

REFERENCE EXAMPLES AND EXAMPLES

The following reference examples and examples illustrate the present invention, but shot not be construed as limiting the present invention.

In the reference examples and examples, "TLC", "NMR", "IR" and "Mass" represent "Thin layer chromatography", "Nuclear magnetic resonance spectrum", "Infrared absorption spectrum" and "Mass spectrum", respectively.

The solvents in the parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations.

Unless otherwise specified, "IR" was measured by the KBr tablet method and "NMR" was measured in a mixture of chloroform-d and ethanol-d₄ respectively.

Reference example 1 Synthesis of 3-(m-methoxy-p-pentyloxycinnamoyl)aminopyrocatechol ##STR69##

Oxyalyl chloride (4.5 ml) was added to m-methoxy-p-pentyloxybenzoic acid (528 mg). In an atmosphere of argon, the solution was stirred for 30 min at room temperature and then concentrated under reduced pressure. The residue was dissolved into methylene chloride (10 ml). In an atmosphere of argon, the solution was dropped to a solution of 3-aminopyrocatechol (275 mg) in a mixture of methylene chloride (10 ml) and pyridine (3 ml) cooling with ice, and the solution was stirred for 1 hr at the same temperature. After stirring for 2 hrs at room temperature, the solution was poured into 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. Solids obtained was washed with hexane, and dried to give the title compound (700 mg) having the following physical data:

TLC: Rf 0.20 (ethyl acetate: hexane=1:2);

NMR (CDCl₃): δ 10.00 (1H, s), 7.75 (1H, d), 7.60 (1H, s), 6.30-7.25 (7H, m), 6.10 (1H, s), 4.10(2H, t), 1.90(3H, s);

Mass: m/e 371 (M⁺), 247, 177, 145, 125, 117, 89.

Reference example 2 Synthesis of 8-(m-methoxy-p-pentyloxycinnamoyl)amino-1,4-dioxane-2-carbonitrile ##STR70##

Dry potassium carbonate (770 mg) and 2-chloroacrylonitrile (0.30 ml) were added to a solution of 3-(m-methoxy-p-pentyloxycinnamoyl) aminopyrocatechol (690 ml; synthesized in reference example 1) in acetone (10 ml). In an atmosphere of argon, the mixture was refluxed for 3 hrs. The reaction mixture cooled to room temperature was poured into ice-water (50 ml). The mixture was extracted with ethyl acetate. The extract was dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride: ethyl acetate=10:1) to give the title compound (565 mg) having the following physical data:

TLC: Rf 0.15 (ethyl acetate: hexane=1:2);

NMR (CDCl₃): δ 8.25(1H, dd), 7.70(1H, d), 7.55(1H, s), 7.00-7.25 (2H, m), 6.90 (1H, d), 6.85 (1H, d), 6.70 (1H, dd), 6.45 (1H, d), 5.20 (1H, dd), 4.30-4.55(2H, m), 4.05(2H, t), 3.93(3H, s);

Mass: m/e 422(M+), 247, 177, 145, 117.

Reference example 3 (Example A) Synthesis of 8- (p-pentylcinnamoyl) amino-1,4-benzodioxane-2-acetic acid methyl ester ##STR71##

Potassium carbonate (509 mg) was added to a solution of 3- (p-pentylcinnamoyl) aminopyrocatechol (300 rag; synthesized by the same procedure as reference example 1) and 4-bromo-2-butenoic acid methyl ester in acetone (10 ml), and the mixture was refluxed for 10 min. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The extract was purified by column chromatography on silica gel (hexane: ethyl acetate=5:1) to give the title compound (341 mg).

Reference example 4 Synthesis of 8- (p-pentylcinnamoyl) amino-1,4-benzodioxane-2-acetamide ##STR72##

8-(p-pentylcinnamoyl)amino-l,4-benzodioxane-2-acetic acid methyl ester (341 mg; synthesized in reference example 3) was dissolved into ethanol which was saturated with ammonia (20 ml). The solution was allowed to stand for 3 days at 100° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate=2:1) to give the title compound (191 mg).

Reference example 5 Synthesis of 8- (p-pentylcinnamoyl) amino-1,4-benzodioxane-2-acetonitrile ##STR73##

Trifluoroacetic anhydride (0.1 m) was added to a solution of 8-(p-pentylcinnamoyl)amino-l,4-benzodioxane-2-acetamide (191 mg; synthesized in reference example 4) in THF (10 ml) cooling with ice. And pyridine (0.02 ml) was added to the mixture. After stirring for 10 min, the mixture was poured into water. The mixture was extracted with ethyl acetate. The extract was dried, concentrated under reduced pressure to give the title compound.

Example 1 Synthesis of 8-[p- (3Z-hexenyloxy) benzoyl]amino-2-(5-tetrazolyl) -1,4-benzodioxane ##STR74##

A mixture of p-(3Z-hexenyloxy)benzoic acid (110 mg) and oxalyl chloride (1 ml) was stirred for 1 hr at room temperature. From the mixture, excess oxalyl chloride was removed under reduced pressure. The residue was dried in vacuo, and then dissolved into methylene chloride (2 ml). In an atmosphere of argon, the solution was dropped into a solution of 8-amino-2- (5-tetrazolyl) -1,4-benzodioxane hydrochloride (128 mg) in a mixture of methylene chloride (2 ml) and pyridine (0.7 ml). The solution was stirred for 5 hrs at room temperature. The solution was diluted with ethyl acetate. The diluted solution was poured into 1N hydrochloric acid (1 ml). The mixture was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized from benzene to give the title compound (112 mg) having the following physical data:

TLC : Rf 0.57 (chloroform: methanol=3: 1);

NMR: δ 7.90(2H, d), 7.88(1H, m), 7.46(1H, dd), 6.96 (2H, d), 6.92 (1H, t), 6.78 (1H, dd), 5.77 (1H, dd), 5.70 (2H, m), 4.61 (2H, m), 4.04 (2H, t), 2.57 (2H, dt), 2.12 (2H, m), 1.01 (3H, t);

IR: 3600-2300, 1650, 1610, 1540, 1505, 1460, 1250, 1175, 1090, 840, 770 cm⁻¹ ;

Mass: m/e 421 (M⁺), 203;

Appearance: white powder.

Example 1 (1)-1 (121)

By the same procedure as example 1, using with a corresponding carboxylic acid and 8-amino-2-(5-tetrazolyl)-1,4-benzodioxane hydrochloride, following compounds having the following physical data, shown in table [VIII] were given ##STR75##

    TABLE VIII        Substituent R Rf value in TLC     Example in the general (developing       Appear- No. formula (Im) solvent) NMR (δ ppm) IR (νcm.sup.-1)      Mass ance               1(1)       0.51(methylenechloride:meth-anol = 3:1) 7.87(2H, d), 7.50(1H, dd),      6.92(1H, t),6.77(1H, dd), 5.80(1H, dd), 4.68-4.54(2H,m), 2.68(2H, t),      1.74-1.54(2H, m),1.50-1.20(4H, m), 0.99(3H, t) 3400˜2400, 1640,1610      , 1540, 1460 393(M.sup.+),243, 175 whitepowder       1(2)      ##STR76##       0.52(methylenechloride:meth-anol = 4:1) 7.83(2H, d), 7.49(1H, dd),      7.33(2H, d),6.91(1H, t), 6.75(1H, dd), 5.76(1H, dd),4.60(2H, m),      2.98(2H, t), 1.70(2H, m),1.39(4H, m), 0.90(3H, t) 3600˜2300,      1635,1620, 1595, 1545,1460, 1340, 1280, 1265, 1100, 780 425, 207      whitepowder       1(3)      ##STR77##       0.47(methylenechloride:meth-anol = 4:1) 7.68(1H, d), 7.46(2H, d),      7.26(2H, d),6.89(1H, t), 6.73(1H, dd), 6.72(1H, d),5.71(1H, dd),      4.68(1H, dd), 4.49(1H, dd),2.95(2H, t), 1.68(2H, m), 1.39(4H, m),0.90(3H,       t) 3600˜2300, 1660,1620, 1595, 1545,1460, 1265, 1200,1090, 970,      820 451(M.sup.-)233 paleyellowcrystal       1(4)      ##STR78##       0.51(methylenechloride:meth-anol = 17:3) 7.69(2H, m), 7.53(2H, d),      6.98(2H, d),6.90(1H, t), 6.73(1H, dd), 6.58(1H, d),5.71(1H, dd),      4.70(3H, m), 4.48(1H, dd),2.24(2H, m), 1.14(3H, t) 3600˜2200,      1      1640,605, 1530, 1510,1450, 1260, 1170,995, 820 449(M.sup.+)231, 219      yellow powder       1(5)      ##STR79##       0.40(methylenechloride:meth-anol = 17:3) 7.69(2H, m), 7.50(2H, d),      6.90(1H, t),6.89(2H, d), 6.72(1H, dd), 6.62(1H, d),5.72(1H, dd),      4.67(1H, dd), 4.49(1H, dd),3.98(2H, t), 1.79(2H, m), 1.36(6H, m),0.90(3H,       t) 3600˜2100, 1640,1600, 1540, 1500,1440, 1255, 1190,1160, 1090,      960815, 760, 700 449(M.sup.+)231, 219 whitepowder       1(6)      ##STR80##       0.26(chloro-form:meth-anol = 3:1) (CDCl.sub.3)8.23(1H, s), 7.79(2H, d),      7.22(2H, d),7.05(1H,d), 6.84(1H, t), 6.72(1H, d), 5.69(1H,m), 4.74(1H,      dd), 4.46(1H, dd), 2.64(2H,t), 1.60(2H, m), 1.15-1.45(12H, m),0.87(3H,      t) 2930, 2860, 2740,1635, 1610, 1540,1450, 1325, 1275,1090, 1040, 900,      850, 770, 715, 595 449(M.sup.+)299, 231,145, 131,118, 91 whitepowder      1(7)       ##STR81##       0.26 (chloro-form:meth-anol = 3:1) (CDCl.sub.3)8.12(1H, s), 7.81(2H,      d), 7.25(2H, d),7.02(1H,d), 6.85(1H, t), 6.75(1H, d), 5.72(1H,m),      4.80(1H, dd), 4.47(1H, dd), 2.66(2H,t), 1.60(2H, m), 1.15-145(14H,      m),0.87(3H, t) 2930, 2860, 1640,1620, 1605, 1540,1470, 1335, 1285,1270,      1100, 1050, 920, 780 463(M.sup.+)327, 259,131, 118,91 whitepowder  1(8)       ##STR82##       0.26(chloro-form:meth-anol = 4:1) (CDCl.sub.3)7.94(1H, s), 7.84(2H, d),      7.30(2H, d),6.70-7.00(3H, m), 5.76(1H, m), 4.92(1H,dd), 4.50(1H, dd),      2.68(2H, t), 1.63(2H,m), 1.15-1.45(16H, m),0.88(3H, t) 2930, 2850,      1640,1615, 1545, 1460,1330, 1280, 1265,1095, 775 477(M.sup.+)327,      259,131, 118, 91 whitepowder       1(9)      ##STR83##       0.26(chloro-form:meth-anol = 4:1) (CDCl.sub.3)7.97(1H, s), 7.84(2H, d),      7.28(2H, d),6.70-7.00(3H, m), 5.74(1H, m), 4.90(1H,dd), 4.49(1H, dd),      2.68(2H, t), 1.63(2H,m), 1.15-1.45(18H, m) 2930, 2850, 1640,1615, 1545,      1460,1335, 1280, 1265,1090, 775 491(M.sup.+)341, 273, 131, 118, 91      whitepowder       1(10)      ##STR84##       0.46(chloro-form:meth-anol = 3:1) 7.70(2H, m), 7.54(2H, d), 6.94(2H,      d)6.91(1H, t), 6.74(1H, dd), 6.68(1H, d),6.05(1H, m), 5.74(1H, dd),      5.38(2H, m)4.70(1H, dd), 4.59(2H, d), 4.51(1H, dd) 3600-2200, 1650,1605,      1540, 1510,1455, 1260, 1200,1170, 1100, 1020,980, 960, 820,780, 715      405(M.sup.+)219, 187 yellowpowder       1(11)      ##STR85##       0.45(chloro-form:meth-anol = 3:1) 7.71(2H, m), 7.56(2H, d), 6.94(3H,    6      m),.77(1H, m), 6.72(1H, d), 5.79(1H, m),4.72(1H, dd), 4.03(2H, m),      1.82(2H, m),1.35(8H, m), 0.92(3H, m) 3600-2200, 1650,1595, 1440,      1260,1170, 1090, 960,820 463(M.sup.+)245, 231,219 yellow powder  1(12)       ##STR86##       0.39(chloro-form:meth-anol = 3:1) 7.89(2H, d), 7.46(1H, dd), 6.88(2H,      d),6.81(1H, t), 6.75(5H, dd), 5.77(1H, dd),4.62(2H, m), 4.04(2H, t),      1.80(2H, m),1.51(2H, m), 0.90(3H, t) 3600-2300, 1630,1600, 1540,      1500,1450, 1250, 1170,1085, 840, 770 395(M.sup.+)177 white powder  1(13)       ##STR87##       0.46(chloro-form:meth-anol = 3:1) 7.89(2H, m), 7.46(1H dd), 6.96(2H,    6      d),.92(1H, ), 6.76(1H, dd), 5.76(1H, dd),4.62(2H, m), 4.02(2H, t),      1.81(2H, m),1.26(10H, m), 0.88(3H, t) 3600-2300, 1630,1605, 1540,      1505,1460, 1260, 1180,1090, 840, 770 465(M.sup.+)247 whitepowder  1(14)       ##STR88##       0.42(chloro-form:meth-anol = 0.42 7.72(1H, d), 7.64(1H, m), 7.48(2H,    7      d),.36(2H, s), 7.22(6H, m), 6.90(1H, t), 6.73(1H, dd), 6.72(1H, d),      4.70(1H, dd),4.67(1H, dd), 4.49(1H, dd), 3.99(2H, s) 3600-2300, 1640,1600      , 1540, 1450,1255, 1200, 1090,970, 960, 730,690 439(M.sup.+)259, 221      whitepowder       1(15)      ##STR89##       0.44(chloro-form:meth-anol = 3:1) 7.72(1H, d), 7.66(1H, m), 7.49(2H,    7      d),.23(2H, d), 6.90(1H, t), 6.75(1H, d),6.74(1H, dd), 5.72(1H, dd),      4.68(1H, dd),4.49(1H, dd), 2.53(1H, m), 1.86(5H, m),1.40(5H, m) 3600-2300      , 1650,1600, 1540, 1480,1455, 1260, 1210,1090, 980, 960,820, 690      431(M.sup.+)219, 213 yellowpowder       1(16)      ##STR90##       0.30 (chloro-form:meth-anol = 5:1) 7.74(1H, d), 7.48(2H, d), 6.88(2H,      d),6.88(1H, t), 6.74(1H, dd), 7.44(1H, s),5.72(1H, t), 4.62(2H, d),      4.01(2H, t) 1660, 1610, 1580,1540, 1515, 1460 435(M.sup.+)217 whitepowder       1(17)      ##STR91##       0.30(methylenechloride:meth-anol = 5:1) 7.40(2H, d), 7.36(1H, d),      7.18(2H, d),6.89(1H, t), 6.74(1H, dd), 6.27(1H, d),57.4(1H, t), 4.72-4.50      (2H, m) 3300, 3200-2300,1660, 1610, 1540,1460 433(M.sup.+)215 whitepowder       1(18)      ##STR92##       0.48(chloro-form:meth-anol = 3:1) 7.69(1H, d), 7.63(1H, m), 7.51(2H,    6      d),.90(2H, d), 5.90(1H, m), 5.72(1H, dd),5.16(2H, m), 4.68(1H, dd),      4.49(1H, dd),4.04(2H, t), 2.56(2H, dt) 3600-2300, 1650,1600, 1540,      1505,1450, 1255, 1200,1170, 1095, 1020,960, 820 419(M.sup.+)219, 201     y      paleellowpowder       1(19)      ##STR93##       0.51(chloro-form:meth-anol = 3:1) 7.69(1H, d), 7.64(1H, m), 7.51(2H,    6      d),.90(1H, t), 6.89(2H, d), 6.73(1H, dd),6.63(1H, d), 5.72(1H, dd),      4.68(1H, dd),4.50(1H, dd), 3.98(2H, t), 1.80(2H, m),1.62(1H, m),      1.36(2H, m), 0.92(6H, d) 3600-2200, 1650,1600, 1540, 1505,1450, 1260,      1165,1095, 960, 820 449(M.sup.+)231, 219 whitepowder       1(20)      ##STR94##       0.26(chloro-form:meth-anol = 3:1) (CDCl.sub.3)7.75-7.95(3H, m),      6.70-7.05(5H, m),5.76(1H, m), 4.98(1H, dd), 4.50(1H, dd),3.99(2H, t),      1.85(2H, m), 1.06(3H, t) 2970, 2870, 2730,1630, 1600, 1540,1505, 1460,      1330,1280, 1255, 1175,1100, 840, 780 381(M.sup.+)231, 163,121, 93,65      whitepowder       1(21)      ##STR95##       0.26(chloro-form:meth-anol = 3:1) (CDCl.sub.3)7.94(1H, s), 7.87(2H, d),      6.70-7.10(5H,m), 5.75(1H, m), 4.88(1H, dd), 4.50(1H,dd), 4.01(2H, t),      1.82(2H, m),1.20-1.60(6H, m), 0.92(3H, t) 3420, 2930, 2860,1635, 1605,      1540,1505, 1460, 1255,1175, 1090, 840,775 423(M.sup.+)395, 273,205,      177,121 whitepowder       1(22)      ##STR96##       0.26(chloro-form:meth-anol = 3:1) (CDCl.sub.3)7.80-8.00(2H, m),      6.70-7.05(5H, m),5.74(1H, m), 4.90(1H, dd), 4.49(1H,dd), 4.00(2H, t),      1.80(2H, m),1.15-1.70(8H, m), 0.89(3H, t) 3420, 2930, 2860,1640, 1605,      1550,1510, 1460, 1260,1180, 1100, 845,775 437(M.sup.+)287, 219,121, 93      whitepowder       1(23)      ##STR97##       0.26(chloro-form:meth-anol = 3:1) (CDCl.sub. 3)7.75-8.00(3H, m),      6.70-7.05(5H, m),5.74(1H, m), 4.90(1H, dd), 4.48(1H,dd), 4.00(2H, t),      1.80(2H, m),1.10-1.60(10H, m), 0.88(3H, t) 3430, 3320, 2930,2850, 2730,      1635,1605, 1545, 1505,1460, 1320, 1255,1180, 1090, 840, 770 451(M.sup.+)3      96, 301,233, 121,93 whitepowder       1(24)      ##STR98##       0.26(chloro-form:meth-anol = 3:1) (CDCl.sub.3)7.75-8.00(3H, m),      6.70-7.05(5H, m),5.76(1H, m), 4.94(1H, dd), 4.50(1H,dd), 4.02(2H, t),      1.80(2H, m),1.10-1.70(14H, m), 0.88(3H, t) 3420, 2930, 2850,1640, 1610,      1545,1510, 1460, 1260,1180, 1100, 845,775 479(M.sup.+)261, 121,93      whitepowder       1(25)      ##STR99##       0.26(chloro-form:meth-anol = 3:1) (CDCl.sub.3)7.94(1H, s), 7.86(2H,      d),6.70-7.10(5H, m), 5.74(1H, m), 4.87(1H, dd), 4.48(1H, dd), 4.04(2H,      t),1.60-1.95(3H, m), 0.98(6H, d) 3420, 2960, 2870,1635, 1605, 1540,1505,      1460, 1260,1180, 1100, 840,775 409(M.sup.+)191, 12193 whitepowder  1(26)       ##STR100##       0.26(chloro-form:meth-anol = 3:1) (CDCl.sub.3)7.88(2H, d), 7.83(1H,      s),6.75-7.10(5H, m), 5.76(1H, m),4.96(1H, dd), 4.50(1H, dd), 4.01(2H,    1      t),.20-1.95(5H, m), 0.93(6H, d) 3420-2960, 2870,1640, 1610, 1545,1510,      1460, 1260,1180, 1100, 845,775 423(M.sup.+)381, 205,161, 121,93 whitepowd      er       1(27)      ##STR101##       0.53(chloro-form:meth-anol = 3:1) 7.48(2H, m), 7.32(2H, d), 6.82(4H,    6      m),.75(1H, t), 6.65(1H, dd), 6.14(1H, d),5.63(1H, dd), 4.59(1H, dd),      4.42(1H, dd),3.86(2H, t), 1.74(2H, m), 0.97(3H, t) 3600-2300, 1650,1600,      1440, 1250,1160, 1120, 1090,980, 830, 760 433(M.sup.+)215 yellowpowder      1(28)       ##STR102##       0.49(chloro-form:meth-anol = 3:1) 7.58(2H, m), 7.39(2H, d), 7.27(2H,    6      d),.92(3H, m), 6.74(1H, dd), 6.28(1H, d),5.72(1H, dd), 4.68(1H, dd),      4.51(1H, dd),2.62(2H, t), 1.60(2H, m), 1.36(2H, m),0.94(3H, t) 3600-2200,       1650,1600, 1530, 1440,1260, 1095, 990,835 431(M.sup.+) 219, 213      yellowpowder       1(29)      ##STR103##       0.30(methylenechloride:meth-anol = 5:1) 7.89(2H, d), 7.23(1H, dd),      6.96(2H, d),6.90(1H, t), 6.77(1H, dd), 6.02(5.80,(1H, m), 5.80-5.74(1H,      m), 5.26-5.08,(2H, m), 4.84-4.50(2H, m) 3500-2300, 1635,1605, 1540,      1      1505,455, 1250 393(M.sup.+)191, 175 whitepowder       1(30)      ##STR104##       0.65(chloro-form:meth-anol = 3:1) 7.70(1H, d), 7.61(1H, m), 7.51(2H,    6      d),.90(1H, t), 6.89(2H, d), 6.73(1H, dd),6.64(1H, d), 5.72(1H, dd),      5.50(2H, m),4.68(1H, dd), 4.50(1H, dd), 4.00(2H, t),2.55(2H, m),      2.10(2H, m), 1.00(3H, t) 3600-2100, 1650,1600, 1500, 1440,1250, 1160,      1090,1010, 960, 820 447(M.sup.+)229, 219 yellowpowder       1(31)      ##STR105##       0.40(methylenechloride:meth-anol = 4:1) 7.31(1H, d), 7.48(1H, d),      7.48(2H, d),6.89(1H, t), 6.87(2H, d), 6.74(1H, dd),6.56(1H, d), 5.80-5.68      (1H, m),4.70-4.30(3H, m), 1.30(3H, d) 3500-2300, 1660,1605, 1540,      1515,1460, 1260 435(M.sup.+)217 paleyellowpowder       1(32)      ##STR106##       0.61(chloro-form:meth-anol = 3:1) 7.72(1H, d), 7.62(1H, m), 7.51(2H,    6      d),.92(2H, d), 6.91(1H, t), 6.74(1H, dd),6.62(1H, d), 5.68(3H, m),      4.60(4H, m),2.18(4H, m), 2.18(2H, m), 1.04(3H, t) 3600-2200, 1645,1600,      1540, 1505,1450, 1260, 1165,1100, 820 50L433(M.sup.+)287, 219,215      yellowpowder       1(33)      ##STR107##       0.42(chloro-form:meth-anol = 3:1) 7.87(2H, d), 7.38(1H, dd), 6.93(2H,      d),6.90(1H, t), 5.75(1H, dd), 4.68(1H, dd),4.55(1H, dd), 4.46(1H, m),      1.72(2H, m),1.46(2H, m), 1.31(3H, d), 0.94(3H, t) 3600-2300, 1630,1600,      1540, 1500,1455, 1250, 1180,1100, 840, 770 409(M.sup.+)219, 191 whitepowd      er       1(34)      ##STR108##       0.44(chloro-form:meth-anol = 3:1) 7.92(2H, d), 7.45(1H, dd), 7.05(2H,      d),6.92(1H, t), 6.77(1H, dd), 5.76(1H, dd),4.75(2H, t), 4.64(2H, m),      2.22(2H, m),1.50(2H, m), 1.32(4H, m), 0.88(3H, t) 3600-2200, 1635,1600,      1540, 1500,1450, 1260, 1220,1170, 1080, 990,835, 760 447(M.sup.+)229,      219 paleyellowpowder       1(35)      ##STR109##       0.46(chloro-form:meth-anol = 3:1) 7.90(2H, d), 7.45(1H, dd), 6.98(2H,      d),6.92(1H, t), 6.76(1H, dd), 5.76(1H, dd),5.69(2H, m), 4.64(4H, m),      2.14(2H, m),1.40(2H, m), 1.32(4H, m), 0.89(3H, t) 3600-2300, 1630,1600,      1500, 1450,1240, 1165, 1080,830, 760 449(M.sup.+)329, 231,219 paleyellows      olid       1(36)      ##STR110##       0.10chloro-form:meth-anol = 4:1) (CDCl.sub.3)7.80-8.00(3H, m), 7.32(2H,      d), 7.19(2H,d), 6.70-7.10(5H, m), 5.74(1H,m), 5.08(2H, s), 4.89(1H, dd)      3420, 2930, 2850,1630, 1605, 1540,1500, 1455, 1245,1170, 1090, 840,770      485(M.sup.+) 399, 365,339, 267253, 219147, 131 whitepowder  1(37)       ##STR111##       0.35(methylenechloride:meth-anol = 5:1) 7.90(2H, d), 7.34(1H, dd),      6.98(2H, d),6.92(1H, t), 6.78(1H, dd), 6.00-5.60(3H,m), 4.80-4.50(4H, m) 3      400, 3200-2300,1630, 1595, 1540,1500, 1450, 1240 463(M.sup.+)343,      245,219, 121 palebrownpowder       1(38)      ##STR112##       0.30(methylenechloride:meth-anol = 5:1) 7.73(1H, d), 7.49(2H, d),      6.90(2H, d),6.90(1H, t), 6.75(1H, dd), 6.58(1H, d),6.00-5.60(3H, m),      4.70-4.40(4H, m) 3350, 3100-23001650, 1595, 1530,1500, 1450, 1260      489(M.sup.+)379, 343,271 whitepowder       1(39)      ##STR113##       0.40(benzene:dio-xan:aceticacid = 20:10:1) 7.9(2H, d), 7.5-7.3(1H, m),      7.0-6.7(4H,m), 5.78(1H, m), 4.7-4.5(2H, m),3.8(2H, m), 2.0-1.6(6H, m),      1.4-1.0(5H,m) 2920, 2850, 1620,1600 435(M.sup.+)217 whitepowder  1(40)       ##STR114##       0.4(benzene:dio-xan:aceticacid = 20:10:1) 7.9(2H, d), 7.5-7.3(1H, m),      7.0-6.7(4H,m), 5.75(1H, m), 4.8-4.5(2H, m),4.0(2H, t), 3.55(2H, t),      1.8(4H, s),1.5(4H, s) 2950, 2850, 1630,1600, 1460, 1250 457(M.sup.+)239      whitepowder       1(41)      ##STR115##       0.4(benzene:dio-xan:aceticacid ≦ 20:10:1 7.9(2H, d), 7.5-7.3(1H,      m), 7.0-6.7(4H,m), 5.75(1H, m), 4.8-4.5(2H, m),4.05(2H, t), 3.65(2H, t),      1.85(4H, s),1.7(2H, s) 2950, 2850, 1630,1600, 1460, 1250 443(M.sup.+)225 w      hitepowder       1(42)      ##STR116##       0.4(benzene:dio-xan:aceticacid ≦       20:10:1) 7.9(2H, d), 7.5-7.3(1H, m), 7.0-6.7(4H,m), 5.78(1H, m),      4.8-4.5(2H, m),4.1(2H, s), 3.65(2H, t), 2.6(4H, s) 1670, 1640, 1490,1290      -- whitepowder       1(43)      ##STR117##       0.10(chloro-form:meth-anol = 4:1) 7.98(1H, d), 7.82(1H, dd), 7.28(1H,      m),7.00(1H, d), 6.90(1H, t), 6.78(1H, dd),5.60-6.00(3H, m), 4.45-4.85(4H,       m),2.10(2H, m), 1.20-1.50(6H, m),0.88(3H, t) 2930, 2860, 1640,1615,      1600, 1545,1500, 1460, 1270,1100, 1060, 980,780 483(M.sup.+)373,      329,265, 219,155, 149 whitepowder       1(44)      ##STR118##       0.4(benzene:dio-xan:aceticacid = 20:10:1) 7.7(1H, d), 7.6-7.4(3H, m),      7.0-6.8(3H,m), 6.75(1H, d), 6.6(1H, d), 5.7(1H, s),sd,21 4.8-4.4(2H, m),      4.0(2H, t), 3.55(2H, t) 2900, 1640, 1600,1530, 1500, 1480,1450 265      palebrownpowder       1(45)      ##STR119##       0.4(benzene:dio-xan:aceticacid = 20:10:1) 7.7(1H, d), 7.6-7.4(3H, m),      7.0-6.8(3H,m), 6.75(1H, d), 5.7(1H, s), 4.8-4.4(2H,m), 4.0(2H, t),      2.0-1.6(6H, m),1.5-0.9(5H, m) 3300, 2920, 1650,1600, 1510, 1450,1250      461(M.sup.+)243 palebrownpowder       1(46)      ##STR120##       0.4(benzene:dio-xan:aceticacid = 20:10:1) 7.75(1H, d), 7.6-7.4(3H, m),      7.0-6.8(3H,m), 6.75(1H, d), 6.6(1H, d), 5.75(1H, s),4.8-4.5(2H, m),      4.05(2H, s), 3.7(2H, s) 2950, 1650, 1600,1540, 1500, 1450,1250 237      palebrownpowder       1(47)      ##STR121##       0.4(benzene:dio-xan:acetic acid = 20:10:1) 7.7(1H, d), 7.6-7.4(3H, m),      7.0-6.8(3H,m), 6.8-6.7(1H, m), 6.6(1H, d),6.7(1H, m), 4.8-4.4(2H, m),      4.0(2H, t),3.6(2H, t) 2950, 1650, 1600,1540, 1500, 1450,1250 252      whitepowder       1(48)      ##STR122##       0.30(methylenechloride:meth-anol = 5:1) 7.88(2H, d), 7.26(1H, dd),      6.97(2H, d),6.90(1H, t), 6.77(1H, dd), 6.00-5.60(3H,m), 4.80-4.50(4H, m) 3      300, 3300-2300,1640, 1610, 1550,1510, 1460, 1260 421(M.sup.+)301,      219,203 paleyellowpowder       1(49)      ##STR123##       0.38(methylenechloride:meth-anol = 5:1) 7.85(2H, d), 7.20(1H, dd),      6.92(2H, d),6.87(1H, t), 6.73(1H, dd), 5.80-5.68(1H,m), 5.65-5.33(2H,      m), 4.66(1H, dd),4.52(1H, dd) 3420, 3300,3300-2200, 1630,1600, 1540,      1500,1460, 1250, 840,770 435(M.sup.+)409, 217,191 whitepowder  1(50)       ##STR124##       0.25chloro-form:meth-anol =       4:1) 7.45-7.80(3H, m), 7.36(1H, dd),6.80-7.00(2H, m), 6.72(1H, dd),      6.60(1H,d), 5.70(1H, m), 4.66(1H, dd), 4.51(1H,dd), 4.04(2H, t),      1.85(2H, m),1.30-1.60(4H, m), 0.95(3H, t) 3350, 2940, 2860,1660, 1610,      1600,1530, 1495, 1455,1265, 1200, 1100,1060, 970, 915,850, 810 469(M.sup.      +)251, 219,181, 153,69 palebrownpowder       1(51)      ##STR125##       0.25(chloro-form:meth-anol = 4:1) (CDCl.sub.3)7.80-8.05(3H, m),      7.15-7.45(4H, m),6.70-7.15(5H, m), 5.76(1H, m), 5.13(2H,s), 4.93(1H,      dd), 4.50(1H, dd), 2.67(2H,t), 1.90(1H, s), 1.64(2H, m), 1.34(4H,      m),0.88(3H, t) 3400, 2940, 2860,1640, 1610, 1540,1500, 1460, 1380,1320,      1255, 1180, 1100, 1005, 900,845, 780 499(M.sup.+)379, 281,219, 181,1569,      161,121, 105,69 whitepowder       1(52)      ##STR126##       0.25(chloro-form:meth-anol = 3:1) (CDCl.sub.3)7.75-8.15(3H, m),      7.10-7.40(4H, m),6.70-7.10(5H, m), 5.73(1H, m), 5.09(2H,s), 4.87(1H,      dd), 4.47(1H, dd), 2.62(2H,t), 1.60(2H, m), 1.35(2H, m), 0.92(3H, t)      3410, 2930, 2860,1635, 1605, 1540,1500, 1455, 1380,1320, 1260, 1180,1100,       900, 840,780 485(M.sup.+)421, 365,301, 267,219, 147,121, 105 whitepowder       1(53)      ##STR127##       0.50(methylenechloride:meth-anol = 5:1) 7.72(2H, d), 7.55(1H, d),      7.50(2H, d),6.90(1H, t), 6.89(2H, d), 6.73(1H, dd),6.59(1H, d), 5.80-5.68      (1H, m),5.38-5.68(2H, m), 4.66(1H, dd), 4.54(1H,dd) 3700-2200, 1650,1600,       1540, 1510,1450, 1260, 1180,1100, 1030, 970,830, 780 461(M.sup.+)436,      315,243, 219,217, 181,147 palegreenpowder       1(54)      ##STR128##       0.50(methylenechloride:meth-anol = 5:1) 7.89(2H, d), 7.30(1H, dd),      6.97(2H, d),6.90(1H, t), 6.77(1H, dd), 6.00-5.60(3H,m), 4.72(1H, dd),      4.60-4.50(3H, m) 3400, 3200-2300,1630, 1600, 1540,1500, 1450, 1250      435(M.sup.+)410, 315 whitepowder       1(55)      ##STR129##       0.44(methylenechloride:meth-anol = 5:1) 7.89(2H, dd), 7.31(1H, dd),      6.96(2H, dd),6.90(1H, t), 6.76(1H, dd), 5.98-5.78(1H,m), 5.78-5.72(1H,      m), 5.14-4.94(2H,m), 4.72(1H, dd), 4.55(1H, dd) 3700-2200, 1640,1610,      1550, 1510,1460, 1280, 1180,1100, 1050, 920,840, 780 407(M.sup.+)189,    1      14721, 93 palegreypowder       1(56)      ##STR130##       0.30(methylenechloride:meth-anol = 5:1) 7.73(1H, d), 7.50(2H, d),      7.50(1H, d),6.91(2H, d), 6.90(1H, t), 6.75(1H, dd),6.58(1H, d), 5.95-5.60      (3H, m),4.72-4.56(2H, m), 4.50(2H, d) 3350, 3100-2300,1660, 1600,      1540,1510, 1460, 1260 461(M.sup.+)315, 243,219, 147 whitepowder  1(57)       ##STR131##       0.51(methylenechloride:meth-anol = 5:1) 7.90(2H, dd), 7.31(1H, dd),      6.98(2H, dd),6.91(1H, t), 6.78(1H, dd), 5.98-5.60(3H,m), 4.74(1H, dd),      4.57(1H, dd),4.54(2H, dd) 3420, 2930,3700-2200, 1640,1610, 1550,      1510,1460, 1320, 1260,1180, 1100, 1050,970, 910, 840,780 477(M.sup.-)259,       219,121, 69 palebrownpowder       1(58)      ##STR132##       0.51(methylenechloride:meth-anol = 3:1) (CDCl.sub.3)7.87(3H, m),      6.89(5H, m), 5.37(1H, m),4.94(1H, m), 4.51(1H, m), 4.01(2H, t),3.97(2H,      t) 3400, 1630, 1600,1530, 500, 1450,1310, 1250, 1170,1090, 1040, 840,770 4      71(M.sup.+)435, 253 whitepowder       1(59)      ##STR133##       0.5(methylenechloride:meth-anol = 3:1) (CDCl.sub.3)7.86(3H, m),      6.86(5H, m), 5.76(1H, m),4.99(1H, m), 4.52(1H, m), 4.01(2H, t),3.53(2H,      t) 3400, 1630, 1600,1520, 1490, 1450,1250, 1170, 1100,1000, 840, 770      485(M.sup.+)449, 267 whitepowder       1(60)      ##STR134##       0.51(methylenechloride:meth-anol = 3:1) (CDCl.sub.3)7.86(3H, m),      6.89(5H, m), 5.76(1H, m),4.98(1H, m), 4.52(1H, m), 4.02(2H, t),3.53(2H,      t) 3400, 1630, 1600,1540, 1500, 1450,1320, 1260, 1170,1090, 1040,      840,770 499(M.sup.+)463, 281 whitepowder       1(61)      ##STR135##       0.45(chloro-form:meth-anol = 3:1) (CDCl.sub.3)7.88(3H, m), 7.40(5H, m),      7.04-6.74(5H,m), 5.76(1H, m), 5.16(2H, s),5.00(1H, m), 4.52(1H, m) 3400,      1620, 1600,1530, 1490, 1450,1320, 1250, 1170,1090, 1000 429(M.sup.+)309      whitepowder       1(62)      ##STR136##       0.5(chloro-form:meth-anol = 3:1) 7.55(4H, m), 7.01-6.70(5H, m),         m      5.85(1H,), 4.60(2H, m), 4.01(2H, t),3.55(2H, t) 3400, 1650, 1590,1530,      1500, 1450,1250, 1170, 1090,960, 820 -- palebrownpowder       1(63)      ##STR137##       0.46(chloroformmethanol =3:1) (CD.sub.3       OD)7.72- 7.30(10H, m), 7.04-6.66(5H, m),5.80(1H, m), 5.23(2H, s),      4.56(2H, m) 3400, 1640, 1590,1490, 1440, 1240,1160, 1090, 990,810, 730      455(M.sup.+) whitepowder       1(64)      ##STR138##       0.30(methylenechloride:meth-anol = 3:1) 7.90(2H, d), 7.30(1H, d),      6.98(2H, d),6.92(1H, t), 6.78(1H, dd), 5.82-5.74(1H,m), 5.56-5.42(1H,      m), 5.14-5.04(1H,m) 3400, 2900,3200-2300, 1635,1605, 1545, 1505,1460,      1260 475(M.sup.+)355, 340,243, 219 whitepowder       1(65)      ##STR139##       0.58(methylenechloride:meth-anol = 5:1) 7.90(2H, dd), 7.32(1H, dd),      6.97(2H, dd),6.91(1H, t), 6.77(1H, dd), 5.96-5.60(4H,nm), 5.10-4.86(2H,      m), 4.72(1H,dd), 4.65-4.40(3H, m) 3600-2200, 1640,1600, 1550, 1510,1560,      1380, 1320,1260, 1180, 1100,1050, 1000, 910,840, 780 447(M.sup.+) 339,      229,219, 121,109, 93,69 whitepowder       1(66)      ##STR140##       0.30(methylenechloride:meth-anol = 5:1) 7.89(2H, dd), 7.30(1H, dd),      6.98(2H, dd),6.91(1H, t), 6.77(1H, dd), 6.04-5.60(3H,m), 4.73(1H, dd),      4.65-4.46(3H, m) 3700-2100, 1640,1600, 1550, 1510,1460, 1380, 1320,1260,      1180, 1100,1050, 1000, 970,900, 840, 780 407(M.sup.+)219, 189,149,      121,93, 69 whitepowder       1(67)      ##STR141##       0.33(methylenechloride:meth-anol = 5:1) 7.73(1H, d), 7.48(2H, d),      7.48(2H, d),6.88(2H, d), 6.89(1H, t), 6.74(2H, dd),6.57(1H, d) -- --      whitepowder       1(68)      ##STR142##       0.47(methylenechloride:meth-anol = 5:1) 7.89(2H, dd), 7.30(1H, dd),      6.96(2H, dd),6.91(1H, t), 6.77(1H, dd), 5.77(1H, s),4.74(1H, dd),      4.56(1H, dd), 4.02(2H, t) 3700-2200, 2960,1640, 1610, 1540,1510, 1460,      1390,1320, 1260, 1180,1100, 1040, 900,840, 780, 720 437(M.sup.+)219,     1      149,21, 93,69 whitepowder       1(69)      ##STR143##       0.37(chloro-form:meth-anol = 4:1) 7.67(1H, d), 7.49(2H, d), 7.28(2H,    6      d),.90(1H, t), 6.74(1H, d), 5.72(1H, dd),4.67(1H, dd), 4.46(1H, dd),      2.62(2H, t),1.59(2H, m), 1.28(6H, m), 0.86(3H, t) 3600-2400, 2210,1610,      1490, 1540,1460, 1330, 1260,1090, 1040, 940,820, 770 431(M.sup.+)219,      213 yellowpowder       1(70)      ##STR144##       0.31(methylenechloride:meth-anol = 5:1) 7.93(1H, d), 7.58(2H, d),      7.58(1H, d),6.90(2H, d), 6.89(1H, t), 6.74(1H, dd),6.54(1H, d) 3300,      3200-2300,1650, 1595, 1540,1505 447(M.sup.+ )301, 245 whitepowder  1(71)       ##STR145##       0.37(methylenechloride:meth-anol = 5:1) 7.89(2H, dd), 7.30(1H, dd),      6.97(2H, dd),6.91(1H, t), 6.77(1H, dd), 6.00-5.60(3H,m), 4.73(1H, dd),      4.56(1H, dd),4.52(2H, d) 3700-2200, 1640,1600, 1550, 1510,1460, 1380,      1320,1260, 1180, 1100,1050, 1000, 970,910, 840, 780,720 393(M.sup.+)339,      219,179, 149,121, 93 whitepowder       1(72)      ##STR146##       0.35(methylenechloride:meth-anol = 5:1) 7.69(1H, d), 7.50(1H, d),      7.40(2H, d),6.88(2H, d), 6.86(1H, t), 6.70(1H, dd),6.55(1H, d) 3500,      3200-2300,1650, 1600, 1530,1500, 1450, 1255 433(M.sup.+)287, 215      paleyellowpowder       1(73)      ##STR147##       0.30(methylenechloride:meth- anol = 5:1) 7.73(1H, d), 7.50(1H, d),      7.48(2H, d),6.88(2H, d), 6,89(1H, t), 6.74(1H, dd),6.58(1H, d) 3350,      3200-2300,1650, 1595, 1530,1505, 1450, 1270 433(M.sup.+)215 paleyellowpow      der       1(74)      ##STR148##       0.20(chloro-form:meth-anol = 4:1) 7.85(2H, d), 7.10-7.40(6H, m),      6.92(2H,d), 6.84(1H, d), 6.73(1H, d), 5.72(1H, m),4.75(1H, dd), 4.50(1H,      dd), 4.21(2H, t),3,11(2H, t) 3420, 3240, 303,2950, 2870, 2740,1605,      1535, 1500,1460, 1250, 1170,1095, 1040, 1020,910, 840, 765 443(M.sup.+)40      8, 225,201, 131,121, 10584 whitepowder       1(75)      ##STR149##       0.20(chloro-form:meth-anol =       4:1) 7.70(1H, d), 7.40(2H, d), 7.15-7.40(6H,m), 6.75-6.90(3H, m),      6.68(1H, d),6.50(1H, d), 5.68(1H, m), 4.45-4.80(2H, m), 4.15(2H, t),      3.08(2H, t) 3400, 3040, 2870,1660, 1605, 1540,1510, 1450, 1260,1200,      1175, 1100,1020, 965, 830, 700. 469(M.sup.+)433, 251,215, 147,105      paleyellowpowder       1(76)      ##STR150##       0.20(chloro-form:meth-anol = 4:1) (CDCl.sub.3)8.00(1H, s), 7.86(2H, d),      7.10-7.40(5H,m), 6.70-7.00(5H, m), 5.74(1H, m),4.88(1H, dd), 4.50(1H,      dd), 4.02(2H, m),2.70(2H, m), 1.85(4H, m) 3400, 3030, 2950,1635, 1605,      1540,1505, 1095, 840,770, 700. 471(M.sup.+)253, 121,91 whitepowder      1(77)       ##STR151##       0.20(chloro-form:meth-anol =       4:1) 7.70(1H, d), 7.45(2H, d), 7.10-7.55(6H,m), 6.80-6.95(3H, m),      6.71(1H, d),6.56(1H, d), 5.70(1H, m), 4.45-4.80(2H,m), 3.97(2H, m),      2.70(2H, m),1.80(4H, m)  3350, 3030, 2950,2870, 1660, 1600,1540, 1510,      1450,1260, 1200, 1175,1105, 970, 830,780 497(M.sup.+)279, 219,147, 91      paleyellowpowder       1(78)      ##STR152##       0.20(chloro-form:meth-anol = 4:1) (CDCl.sub.3)7.97(1H, s), 7.89(2H, d),      7.03(2H, d),6.70-7.00(3H, m), 5.75(1H, m), 4.90(1H,dd), 4.73(2H, m),      4.49(1H, dd), 2.22(2H,t), 1.62(1H, m), 1.40(2H, m), 0.87(6H, d) 3400,      2960, 1635,1605, 1540, 1500,1460, 1260, 1230,1175, 1095, 1000,840, 775      447(M.sup.+)279, 229,147, 121,91 whitepowder       1(79)      ##STR153##       0.45(methylenechloride:meth-anol = 5:1) 7.75(1H, d), 7.51(2H, d),      7.51(1H, d),6.92(2H, d), 6.91(1H, t), 6.76(1H, dd),6.60(1H, d), 6.00-5.62      (3H, m), 4.74-4.44(4H,m) 3700-2200, 1660, 1600, 1550, 1520,1490, 1460,      1260,1180, 1100, 1050,970, 920, 830,780, 720 419(M.sup.+)219, 201,147,      105 paleyellowpowder       1(80)      ##STR154##       0.33(methylenechloride:meth-anol = 5:1) 7.72(1H, d), 7.48(2H, d),      7.44(1H, d),6.89(2H, d), 6.88(1H, t), 6.73(1H, dd),6.55(1H, d), 6.00-5.60      (3H, m),4.70-4.56(2H, m), 4.48(2H, d) 3350, 3200-2300,1650, 1590,      1530,1500, 1440, 1250 503(M.sup.+)357 whitepowder       1(81)      ##STR155##       0.34(methylenechloride:meth-anol = 5:1) 7.88(2H, d), 7.32(1H, dd),      6.95(2H, d),6.90(1H, t), 6.76(1H, dd), 5.80-5.72(1H,m), 4.70(1H, dd),      4.55(1H, dd),4.01(2H, t) 3400, 3200-2300,1630, 1600, 1540,1500, 1460,      1250 251(M.sup.+)233 121 whitepowder       1(82)      ##STR156##       0.30(methylenechloride:meth-anol = 5:1) 7.75(1H, d), 7.50(2H, d),      7.45(1H, d),7.36-7.15(5H, m), 6.91(1H, t), 6.89(2H,d), 6.76(1H, dd),      6.66(1H, d), 5.75(1H,t), 4.63(2H, d), 3.98(2H, t) 3350, 3100-2250,1660,      1500, 1540,1510, 1450, 1260 511(M.sup.+)293 251219 whitepowder  1(83)       ##STR157##       0.35(methylenechloride meth-anol = 5:1) 7.87(2H, d), 7.36-7.11(6H, m),      6.94(2H,d), 6.80(1H, t), 6.76(1H, dd), 5.75(1H,dd), 4.72(1H, dd),      4.55(1H, dd),4.00(2H, t) 3400, 3100-2250,1630, 1600, 1540,1505, 1450,      1300,1260 485(M.sup.+)267 whitepowder       1(84)      ##STR158##       0.45(methylenechloride meth-anol = 5:1) 7.88(2H, d), 7.32(1H, dd),      6.95(2H, d),6.90(1H,t ), 6.76(1H, dd), 5.76(1H, t),4.75-4.50(2H, m),      4.01(2H, t) 3440, 2930, 2850,1640, 1610, 1550,1510, 1460, 1260 477(M.sup.      +)259 231 whitepowder       1(85)      ##STR159##       0.32(methylenechloride meth-anol = 5:1) 7.72(1H, d), 7.48(2H, d),      7.44(1H, d),6.88(1H, t), 6.87(2H, d), 6.73(1H, dd),6.57(1H, d), 5.71(1H,      m), 4.68-4.51(2H,m), 3.97(2H, d) 3430, 2930, 2850,1660, 1600, 1540,1510,      1450, 1260 503(M.sup.+)285 yellowpowder       1(86)      ##STR160##       0.30(methylenechloride:meth-anol = 5:1) 7.72(1H, d), 7.48(2H, d),      6.88(1H, t),6.87(2H, d), 6.73(1H, dd), 6.56(1H, d),0.87(6H, d) 3350,      3200-2300,1655, 1600, 1540,1510, 1450, 1260 477(M.sup.+)259 paleyellowpow      der       1(87)      ##STR161##       0.32(methylenechloride:meth-anol = 5:1) 7.89(2H, d), 7.27(1H, dd),      6.96(2H, d),6.90(1H, t), 6.77(1H, dd), 5.70-5.30(2H,m) 3400, 3200-2300,16      40, 1605, 1545,1500, 1450, 1260 449(M.sup.+)369 231 whitepowder  1(88)       ##STR162##       0.32(methylenechloride:meth-anol = 5:1) 7.89(2H, d), 7.44(2H, d),      7.38(1H, dd),6.91(1H, t), 6.77(1H, dd), 4.55(2H, s) 3350, 3200-2300,1630,       1605, 1535,1450, 1090 437(M.sup.+)287 219 whitepowder       1(89)      ##STR163##       0.45(methylenechloride:meth-anol = 5:1) 7.89(2H, d), 7.36(1H, d),      6.94(2H, d),6.91(1H, t), 6.76(1H, d), 3.68(3H, s) 3325, 3200-2300,1730,      1640, 1610,1460, 1260 467(M.sup.+)391, 322 whitepowder       1(90)      ##STR164##       0.45(methylenechloride:meth-anol = 5:1) 7.82(2H, d), 7.41(1H, dd),      7.32(2H, d),6.91(1H, t), 6.76(1H, d), 2.97(2H, t) 3400, 3200-2300,1645,      1620, 1605,1550, 1460, 1100. 453(M.sup.+)302, 235 whitepowder  1(91)       ##STR165##       0.38(methylenechloride:meth-anol = 5:1) 7.76(1H, d), 7.52(2H, d),      7.34(2H, d),6.88(1H, t), 6.73(1H, dd), 6.70(1H, d),4.50(2H, s), 3.50(2H,      t), 0.90(6H, d) 3370, 3200-2300,1660, 1610, 1545,1460, 1260, 1100      449(M.sup.+)245, 231,219 whitepowder       1(92)      ##STR166##       0.34(methylenechloride:meth-anol = 5:1) 7.72(1H, d), 6.49(2H, d),      7.17(1H, dd),6.00-6.80(6H, m), 6.74(1H, dd), 6.57(1H,d), 4.21(2H, t),      3.32(2H, t) 3350, 3200-2300,1660, 1610, 1540,1510, 1460, 1260,1180, 830       475(M.sup.+)365, 257,219 whitepowder       1(93)      ##STR167##       0.33(methylenechloride:meth-anol = 5:1) 7.50(1H, s), 7.58(1H, d),      7.37(2H, d),6.93(2H, d), 6.84(1H, t), 6.84-6.74(2H,m), 5.80(1H, m),      2.38(3H, d),0.92(6H, d) 3400, 3200-2300,1635, 1600, 1505,1260 463(M.sup.+      )245, 161 whitepowder       1(94)      ##STR168##       0.33(methylenechloride:meth-anol = 5:1) 7.87(2H, d), 7.41(1H, dd),      6.94(2H, dd),6.90(1H, t), 6.74(1H, dd), 4.04(2H, t) 3350, 3200-2300,1630,       1600, 1540,1500, 1450, 1245 449(M.sup.+)406, 393,355, 231 whitepowder      1(95)       ##STR169##       0.34(methylenechloride:meth-anol = 5:1)  7.88(2H, dd), 7.35(1H, dd),      7.17(1H, dd),7.01-6.84(5H, m), 6.75(1H, dd),5.80-5.72(1H, m), 4.68(1H,      dd), 4.55(1H,dd) 3700-2200, 1640,1610, 1540, 1500,1470, 1260, 1180,1100,      900, 840,700 449(M.sup.+)355, 231,219, 149,121, 111 whitepowder  1(96)       ##STR170##       0.35(methylenechoride:meth-anol = 5:1) 7.88(2H, dd), 7.34(1H, dd),      6.94(2H, dd),6.90(1H, t), 6.76(1H, dd), 5.80-5.72(1H,m), 4.69(1H, dd),      4.55(1H, dd) 3600-2200, 1740,1640, 1600, 1550,1510, 1460, 1260,1180,      1100, 1040,850, 780 481(M.sup.+)263, 219,149, 121 whitepowder  1(97)       ##STR171##       0.41(methylenechloride:meth-anol = 5:1) 7.73(1H, d), 7.47(2H, d),      7.38(1H, d), 6.87(1H, t), 6.86(2H, d), 6.73(1H, dd),4.06(2H, t) 3600-2200      , 1740,1660, 1600, 1540,1520, 1460, 1260,1180, 1100, 1040,970, 830      507(M.sup.+)464, 289,219, 121 paleyellowpowder       1(98)      ##STR172##       0.30(methylenechloride:meth-anol = 5:1) 7.72(2H, d), 7.46(1H, d),      6.84(2H, d),6.87(1H, t), 6.72(1H, dd), 6.55(1H, d),5.80-5.66(1H, m),      4.80-4.50(2H, m) 3400, 3200-2300,1655, 1600, 1530,1510, 1450, 1260      475(M.sup.+)381, 223,257, 147 paleyellowpowder       1(99)      ##STR173##       0.41(methylenechloride:meth-anol = 5:1) 7.89(2H, d), 7.34(1H, dd),      6.96(2H, d),6.91(1H, t), 6.77(1H, dd), 4.02(2H, t) 3410, 3150-2250,1640,      1610, 1540,1510, 1460, 1260 449(M.sup.+)231 whitepowder       1(100)      ##STR174##       0.33(methylenechloride:meth-anol =       5:1) 7.79(2H, dd), 7.37(1H, dd),7.35-7.15(5H, m), 6.95(2H, dd),6.92(1H,      t), 6.78(1H, dd), 5.82-5.73(1H,m) 3600-2200, 1630,1600, 1550, 1520,1470,      1330, 1270,1190, 1100, 1040,850, 780, 710 457(M.sup.+)239, 219,121      whitepowder       1(101)      ##STR175##       0.33(methylenechloride meth-anol = 5:1) 7.96(2H, d), 7.52(1H, dd),      7.22(2H, d),7.25-7.14(1H, m), 6.93(1H, t), 6.78(1H,dd), 6.03(1H, d),      5.90-5.70(1H,m), 4.80-4.50(2H, m) 3400, 3200-2300,1730, 1630, 1595,1530,      1200 463(M.sup.+)339, 245,121, 125 whitepowder       1(102)      ##STR176##       0.48(methylenechloride meth-anol = 5:1) 7.89(2H, dd), 7.38(1H, dd),      6.96(2H, dd),6.91(1H, t), 6.76(1H, dd), 5.81-5.73(1H,m), 4.69(1H, dd),      4.56(1H, dd) 3600-2100, 2950,1640, 1600, 1550,1510, 1460, 1320,1260,      1180, 1100,1050, 850 479(M.sup.+)261, 219,121, 93 whitepowder  1(103)       ##STR177##       0.27(methylenechloride meth-anol = 5:1) 7.72(1H, d), 7.50(2H, d),      7.30-7.14(5H,m), 6.90(1H, t), 6.88(2H, d), 6.74(1H,dd), 6.59(1H, d),      5.78-5.68(1H, m),4.68(1H, dd), 4.53(1H, dd) 3700-2100, 1660,1600, 1540,      1510,1450, 1270, 1180,1100, 1030, 980,830, 700 483(M.sup.+)265, 219,147,      119,91 paleyellowpowder       1(104)      ##STR178##       0.25(methylenechloride meth-anol = 4:1) (CDCl.sub.3)8.00(1H, s),      7.87(2H, d), 7.33(2H, d),7.20(2H, d), 7.02(2H, d), 6.98(1H, d),6.86(1H,      t), 6.75(1H, d), 5.74(1H, m),5.10(2H, s), 4.86(1H, dd), 4.48(1H, dd)      3300, 2960, 2870,1620, 1605, 1500,1465, 1250, 1175,1100 471(M.sup.+),482      415,377, 351339, 253,223 219,205, 149133, 121,91 white powder  1(105)       ##STR179##       0.35(methylenechloride meth-anol = 5:1) 7.91(1H, d), 7.45-7.20(6H, m),      7.02(2H,d), 6.91(1H, t), 6.76(1H, dd), 6.74(1H,d), 6.39(1H, dt) 3400,      3200-2300,1630, 1600, 1540,1495, 1450, 1250 455(M.sup.+)335, 281      paleyellowpowder       1(106)      ##STR180##       0.32(methylenechloride:meth-anol = 5:1) 8.06(4H, s), 7.72(1H, dd),      6.97(1H, t),6.80(1H, dd), 5.76(1H, m), 4.65(2H, m),3.00(2H, t) 3300,      3200-2300,1680, 1630, 1530,1460, 1275 449(M.sup.+)299, 231 whitepowder      1(107)       ##STR181##       0.20(chloro-form:methanol =4:1) (CDCl.sub.3)8.03(1H, s), 7.35-7.60(5H,      m), 7.15(1H,s), 6.96(2H, d), 6.60-6.70(5H, m), 5.80(1H,m), 4.97(1H, dd),      4.49(1H, dd),3.89(2H, t) 3390, 2950, 1655,1605, 1540, 1510,1450, 1260,      1175 525(M.sup.+)307, 279,195, 165,121 yellowpowder       1(108)      ##STR182##       0.25(methylenechloride:meth-anol = 5:1) 7.88(2H, d), 7.33(1H, dd),      7.34-7.10(5H,m), 6.94(2H, d), 6.90(1H, t),6.75(1H, dd), 4.12(2H, t)      3460-2210, 1640,1610, 1540, 1510,1460, 1260 489(M.sup.+)271 whitepowder      1(109)       ##STR183##       0.20(chloro-form:meth-anol = 5:1)  (CDCl.sub.3)8.05(1H, s), 7.86(2H,      d), 7.13(1H, dd),6.65-7.05(7H, m), 5.74(1H, m), 4.85(1H,dd), 4.49(1H,      dd), 4.03(2H, m), 2.93(2H,m), 1.90(4H, m) 2950, 1630, 1605,1540, 1500,      1455,1255, 1175, 1090,840, 770, 690 477(M.sup.+)307, 259,139, 121,97     y      paleellowpowder       1(110)      ##STR184##       0.20(chloro-form:meth-anol = 4:1) (CDCl.sub.3)7.96(1H, s), 7.85(2H, d),      7.10-7.35(3H,m), 6.70-7.00(7H, m), 5.72(1H, m),4.86(1H, dd), 4.47(1H,      dd), 4.20(2H, t),4.14(2H, t), 2.28(2H, m) 3400, 2940, 2870,2730, 1630,      1600,1540, 1490, 1460,1250, 1175, 1095,1050, 760, 690 473(M.sup.+)255,      135,121, 107 whitepowder       1(111)      ##STR185##       0.30(methylenechloride:meth-anol = 5:1) 7.88(2H, d), 6.97(3H, d),      6.88(1H, t),6.77(1H, dd), 6.35(1H, dd), 6.07(1H,dd), 5.86-5.65(3H, m),      4.85(1H, dd),4.60(2H, d), 4.52(1H, dd) 3400, 2960, 2930,2860, 1600,      1      1530,500, 1450, 1380,1250 447(M.sup.+)327, 229,219 whitepowder  1(112)       ##STR186##       0.20(chloro-form:meth-anol = 4:1) (CDCl.sub.3)7.94(1H, s), 7.87(2H, d),      6.70-7.00(5H,m), 5.74(1H, m), 4.90(1H, dd), 4.48(1H,dd), 4.02(2H, t),      3.30(2H, t),1.10-2.20(7H, m) 3410, 2940, 2870,2730, 2090, 1635,1600,      1540, 1505,1460, 1260, 1180,1095, 845, 770 450(M.sup.+)232, 121,84      whitepowder       1(113)      ##STR187##       0.43(methylenechloride:meth-anol = 5:1) 7.89(2H, d), 7.39(1H, dd),      6.96(2H, d),6.91(1H, t), 6.76(1H, dd), 4.04(2H, t) 3650-3150, 2940,1630,      1605, 1545,1505, 1460, 1260 (M.sup.+)487269 whitepowder       1(114)      ##STR188##       0.22(methylenechloride:meth-anol = 5:1) 7.87(2H, d), 7.42(1H, dd),      7.36-7.20(5H,m), 6.90(2H, d), 6.90(1H, t),6.76(1H, dd), 4.19(2H, t),      3.30(2H, t) 3400, 3100-2200,1600, 1540, 1500,1460, 1250 475(M.sup.+)257      whitepowder       1(115)      ##STR189##       0.30(methylenechloride:meth-anol = 5:1) 7.92(2H, d), 7.38(1H, d),      7.30(2H, t),7.10-6.87(6H, m), 6.77(1H, dd), 5.77(1H,dd), 4.70(1H, dd),      .456(1H, dd),4.37(4H, s) 3600-2500, 1730,1630, 1605, 1570,1530, 1485,      1460,1380, 1285, 1245,1200 459(M.sup.+)241, 218 yellow powder  1(116)       ##STR190##       0.31(methylenechloride:meth-anol = 5:1) 7.89(2H, d), 7.41(1H, dd),      6.95(2H, d),6.91(1H, t), 6.75(1H, dd), 4.50(2H, t),4.07(2H, t) 3350,      2900, 1630,1605, 1540, 1505,1460, 1260 decom-posed whitepowder  1(117)       ##STR191##       0.30(methylenechloride:meth-anol = 5:1) 7.92(2H, d), 7.46(1H, dd),      7.00(2H, d),6.92(1H, t), 6.76(1H, dd), 5.76(1H, dd),4.64(1H, dd),      4.56(1H, dd), 4.21(2H, t) 3650-3150, 3020-2250, 2100,1635, 1605,      1540,1510, 1480, 1460,1340, 1320, 1310,1280, 1260 408(M.sup.+)339, 190      whitepowder       1(118)      ##STR192##       0.30(methylenechloride:meth-anol = 5:1) 7.90(2H, d), 7.34(1H, dd),      6.95(2H, d),6.92(1H, t), 6.77(1H, dd), 5.77(1H, dd),4.70(1H, dd),      4.56(1H, dd), 4.06(2H, t),3.39(2H, t) 3620-3150, 2920,2100, 1605,      1540,1505, 1460, 1260 436(M.sup.+)218 whitepowder       1(119)      ##STR193##       0.30(methylenechloride:meth-anol = 5:1) 7.86(2H, d), 7.80(3H, m),      7.72(1H, s),7.58(1H, dd), 7.44(3H, m), 6.95(2H, d),6.90(1H, t), 6.73(1H,      dd), 5.68(1H, t),4.55(2H, d) 3700-2300, 1650,1610, 1520, 1510,1455, 1260 4      93(M.sup.+),450, 437,399, 275 whitepowder       1(120)      ##STR194##       0.30(methylenechloride:meth-anol = 5:1)   491(M.sup.+)273, 115,111      p      whiteowder       1(121)      ##STR195##       0.30(methylenechloride:meth-anol = 5:1)   505, 411,287, 253,121      whitepowder

Example 1(201)-1(260)

By the same procedure as example 1, using with a corresponding carboxylic acid and a corresponding 8-amino-2(5-tetrazolyl)-4-oxo-4H-1-benzopyran hydrochloride which have corresponding substituent R³ following compounds having the following physical data, shown in table [IX] were given. ##STR196##

    TABLE IX        Substituent R, R.sup.3 Rf value in TLC     Example in the general      (developing No. formula (In) solvent) NMR (δ ppm) IR (ν      cm.sup.-1) Mass Appearance               1(201)       ##STR197##       ##STR198##       ##STR199##       ##STR200##       ##STR201##       1(202)      ##STR202##       ##STR203##       ##STR204##       ##STR205##       ##STR206##       ##STR207##       1(203)      ##STR208##       ##STR209##       ##STR210##       ##STR211##       ##STR212##       ##STR213##       1(204)      ##STR214##       ##STR215##       ##STR216##       ##STR217##       ##STR218##       ##STR219##       1(205)      ##STR220##       ##STR221##       ##STR222##       ##STR223##       ##STR224##       ##STR225##       1(206)      ##STR226##       ##STR227##       ##STR228##       ##STR229##       ##STR230##       ##STR231##       1(207)      ##STR232##       ##STR233##       ##STR234##       ##STR235##       ##STR236##       ##STR237##       1(208)      ##STR238##       ##STR239##       ##STR240##       ##STR241##       ##STR242##       ##STR243##       1(209)      ##STR244##       ##STR245##       ##STR246##       ##STR247##       ##STR248##       ##STR249##       1(210)      ##STR250##       ##STR251##       ##STR252##       ##STR253##       ##STR254##       ##STR255##       1(211)      ##STR256##       ##STR257##       ##STR258##       ##STR259##       ##STR260##       ##STR261##       1(212)      ##STR262##       ##STR263##       ##STR264##       ##STR265##       ##STR266##       ##STR267##       1(213)      ##STR268##       ##STR269##       ##STR270##       ##STR271##       ##STR272##       ##STR273##       1(214)      ##STR274##       ##STR275##       ##STR276##       ##STR277##       ##STR278##       ##STR279##       1(215)      ##STR280##       ##STR281##       ##STR282##       ##STR283##       ##STR284##       ##STR285##       1(216)      ##STR286##       ##STR287##       ##STR288##       ##STR289##       ##STR290##       ##STR291##       1(217)      ##STR292##       ##STR293##       ##STR294##       ##STR295##       ##STR296##       ##STR297##       1(218)      ##STR298##       ##STR299##       ##STR300##       ##STR301##       ##STR302##       ##STR303##       1(219)      ##STR304##       ##STR305##       ##STR306##       ##STR307##       ##STR308##       ##STR309##       1(220)      ##STR310##       ##STR311##       ##STR312##       ##STR313##       ##STR314##       ##STR315##       1(221)      ##STR316##       ##STR317##       ##STR318##       ##STR319##       ##STR320##       ##STR321##       1(222)      ##STR322##       ##STR323##       ##STR324##       ##STR325##       ##STR326##       ##STR327##       1(223)      ##STR328##       ##STR329##       ##STR330##       ##STR331##       ##STR332##       ##STR333##       1(224)      ##STR334##       ##STR335##       ##STR336##       ##STR337##       211       ##STR338##       1(225)      ##STR339##       ##STR340##       ##STR341##       ##STR342##       ##STR343##       ##STR344##       1(226)      ##STR345##       ##STR346##       ##STR347##       ##STR348##       ##STR349##       ##STR350##       1(227)      ##STR351##       ##STR352##       ##STR353##       ##STR354##       ##STR355##       ##STR356##       1(228)      ##STR357##       ##STR358##       ##STR359##       ##STR360##       ##STR361##       ##STR362##       1(229)      ##STR363##       ##STR364##       ##STR365##       ##STR366##       ##STR367##       ##STR368##       1(230)      ##STR369##       ##STR370##       ##STR371##       ##STR372##       ##STR373##       ##STR374##       1(231)      ##STR375##       ##STR376##       ##STR377##       ##STR378##       ##STR379##       ##STR380##       1(232)      ##STR381##       ##STR382##       ##STR383##       ##STR384##       ##STR385##       ##STR386##       1(233)      ##STR387##       ##STR388##       ##STR389##       ##STR390##       ##STR391##       ##STR392##       1(234)      ##STR393##       ##STR394##       ##STR395##       ##STR396##       ##STR397##       ##STR398##       1(235)      ##STR399##       ##STR400##       ##STR401##       ##STR402##       ##STR403##       ##STR404##       1(236)      ##STR405##       ##STR406##       ##STR407##       ##STR408##       ##STR409##       ##STR410##       1(237)      ##STR411##       ##STR412##       ##STR413##       ##STR414##       ##STR415##       ##STR416##       1(238)      ##STR417##       ##STR418##       ##STR419##       ##STR420##       ##STR421##       ##STR422##       1(239)      ##STR423##       ##STR424##       ##STR425##       ##STR426##       ##STR427##       ##STR428##       1(240)      ##STR429##       ##STR430##       ##STR431##       ##STR432##       ##STR433##       ##STR434##       1(241)      ##STR435##       ##STR436##       ##STR437##       ##STR438##       ##STR439##       ##STR440##       1(242)      ##STR441##       ##STR442##       ##STR443##       ##STR444##       ##STR445##       ##STR446##       1(243)      ##STR447##       ##STR448##       ##STR449##       ##STR450##       ##STR451##       ##STR452##       1(244)      ##STR453##       ##STR454##       ##STR455##       ##STR456##       ##STR457##       ##STR458##       1(245)      ##STR459##       ##STR460##       ##STR461##       ##STR462##       ##STR463##       ##STR464##       1(246)      ##STR465##       ##STR466##       ##STR467##       ##STR468##       ##STR469##       ##STR470##       1(247)      ##STR471##       ##STR472##       ##STR473##       ##STR474##       ##STR475##       ##STR476##       1(248)      ##STR477##       ##STR478##       ##STR479##       ##STR480##       ##STR481##       ##STR482##       1(249)      ##STR483##       ##STR484##       ##STR485##       ##STR486##       ##STR487##       ##STR488##       1(250)      ##STR489##       ##STR490##       ##STR491##       ##STR492##       ##STR493##       ##STR494##       1(251)      ##STR495##       ##STR496##       ##STR497##       ##STR498##       ##STR499##       ##STR500##       1(252)      ##STR501##       ##STR502##       ##STR503##       ##STR504##       ##STR505##       ##STR506##       1(253)      ##STR507##       ##STR508##       ##STR509##       ##STR510##       ##STR511##       ##STR512##       1(254)      ##STR513##       ##STR514##       ##STR515##       ##STR516##       307       ##STR517##       1(255)      ##STR518##       ##STR519##       ##STR520##       ##STR521##       ##STR522##       ##STR523##       1(256)      ##STR524##       ##STR525##       ##STR526##       ##STR527##       307, 121       ##STR528##       1(257)      ##STR529##       ##STR530##       ##STR531##       ##STR532##       275       ##STR533##       1(258)      ##STR534##       ##STR535##         287       ##STR536##       1(259)      ##STR537##       ##STR538##         287       ##STR539##       1(260)      ##STR540##       ##STR541##         273, 121       ##STR542##

Example 1(301)-1(302)

By the same procedure as example 1, using with p-pentylcinnamic acid and 8-amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-dithianaphthalene hydrochloride or 5-amino-2-(5-tetrazolyl) -2,3-dihydro-1,4-dithianaphthalene hydrochloride, following compounds having the following physical data, shown in table [X] were given. ##STR543##

                                      TABLE X                                      __________________________________________________________________________          Rf value in TLC                                                           Example                                                                             (developing                                                               No.  solvent) NMR (δppm)  IR (νcm.sup.-1)                                                                      Mass Appearance                       __________________________________________________________________________     1(301)                                                                              0.33     7.76(1H, d), 7.55(2H, d), 7.44-7.10                                                              3500-2300, 1660,                                                                        451(M.sup.+)                                                                        white                                 (chloroform:                                                                            (3H, m), 7.24(2H, d), 673(1H, d),                                                                1620, 1610, 1565,                                                                       408, 372                                                                            powder                                methanol =                                                                              5.15(1H, m), 3.66(2H, m), 2.64(2H, t),                                                           1510, 1180, 980                                                                         357, 355                                   3:1)     0.90(3H, t)                338, 201                              1(302)                                                                              0.23     7.72(1H, d), 7.51(2H, d), 7.22(2H, d),                                                           3500-2800, 1660,                                                                        201, white                                 (chloroform:                                                                            7.60-7.10(3H, m), 6.71(2H, d),                                                                   1620, 1610, 1560,                                                                       198  powder                                methanol =                                                                              5.40-5.26(1H, m), 3.56-3.40(2H, m),                                                              1510                                                3:1)     2.68(2H, t), 1.64(2H, t), 0.90(3H, t)                            __________________________________________________________________________

Example 1(401)

By the same procedure as example 1, using with p-heptyloxybenzodithioic acid and 8-amino-2-(5-tetrazolyl) -1,4-benzodioxane hydrochloride, following compound having following physical data was given. ##STR544##

TLC: Rf 0.14 (chloroform: methanol=17:3);

NMR: δ 7.87 (2H, d), 7.77 (1H, m), 6.90 (4H, m), 5.74 (1H, m), 4.58 (2H, m), 3.98 (2H, t), 1.78 (2H, m), 1.30 (SH, m), 0.88 (3H, t);

IR: ν 3600-2400, 1600, 1495, 1450, 1255, 1170, 1090, 1005, 960, 830 cm⁻¹ ;

Mass: m/e 453 (M⁺), 420, 354, 326, 235, 219, 137, 121;

Appearance: orange powder.

Example 1 (501)-1 (526)

By the same procedure as example 1, using a corresponding carboxylic acid and a corresponding amine, following compounds having the following physical data, shown in-table [XI] were given.

    TABLE XI       Example Formula Rf value in TLC     No.  (developing solvent) NMR      (δppm) IR (νcm.sup.-1) Mass Appearance               1(501)       ##STR545##       ##STR546##       ##STR547##       ##STR548##       ##STR549##       white powder       1(502)      ##STR550##       ##STR551##       ##STR552##       ##STR553##       ##STR554##       white powder       1(503)      ##STR555##       ##STR556##       ##STR557##       ##STR558##       ##STR559##       yellow powder       1(504)      ##STR560##       ##STR561##       ##STR562##       ##STR563##       ##STR564##       brown powder       1(505)      ##STR565##       ##STR566##       ##STR567##       ##STR568##       ##STR569##       white powder       1(506)      ##STR570##       ##STR571##       ##STR572##       ##STR573##       ##STR574##       white powder       1(507)      ##STR575##       ##STR576##       ##STR577##       ##STR578##       ##STR579##       white powder       1(508)      ##STR580##       ##STR581##       ##STR582##       ##STR583##       ##STR584##       white powder       1(509)      ##STR585##       ##STR586##       ##STR587##       ##STR588##       ##STR589##       white powder       1(510)      ##STR590##       ##STR591##       ##STR592##       ##STR593##       ##STR594##       white powder       1(511)      ##STR595##       ##STR596##       ##STR597##       ##STR598##       ##STR599##       white powder       1(512)      ##STR600##       ##STR601##       ##STR602##       ##STR603##       325, 219       ##STR604##       1(513)      ##STR605##       ##STR606##       ##STR607##       ##STR608##       205, 121       ##STR609##       1(514)      ##STR610##       ##STR611##       ##STR612##       ##STR613##       ##STR614##       yellow powder       1(515)      ##STR615##       ##STR616##       ##STR617##       ##STR618##       ##STR619##       yellow powder       1(516)      ##STR620##       ##STR621##       ##STR622##       ##STR623##       ##STR624##       1(517)      ##STR625##       ##STR626##       ##STR627##       ##STR628##       ##STR629##       white powder       1(518)      ##STR630##       ##STR631##       ##STR632##       ##STR633##       ##STR634##       white powder       1(519)      ##STR635##       ##STR636##       ##STR637##       ##STR638##        yellow powder       1(520)      ##STR639##       ##STR640##       ##STR641##       ##STR642##       ##STR643##       yellow powder       1(521)      ##STR644##       ##STR645##       ##STR646##       ##STR647##       ##STR648##       white powder       1(522)      ##STR649##       ##STR650##       ##STR651##       ##STR652##       ##STR653##       white powder       1(523)      ##STR654##       ##STR655##       ##STR656##       ##STR657##       ##STR658##       ##STR659##       1(524)      ##STR660##       ##STR661##       ##STR662##       ##STR663##       ##STR664##       ##STR665##       1(525)      ##STR666##       ##STR667##       ##STR668##       ##STR669##       ##STR670##       ##STR671##       1(526)      ##STR672##       ##STR673##       ##STR674##       ##STR675##       239 yellow powder

Example 2 Synthesis of 8- (3-methoxy-4-pentyloxycinnamoyl) amino-2-(5-tetrazolyl) -1,4-benzodioxane ##STR676##

Sodium azide (490 mg) and pyridinium chloride (870 rag) were added to a solution of 8-(3-methoxy-4-pentyloxycinnamoyl) amino-1,4-benzodioxane (560 mg; synthesized in reference example 2) in dry dimethylformamide (3 ml). In an atmosphere of argon, the solution was stirred for 1.5 hrs at 100° C. The reaction solution cooled to room temperature was poured into IN hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (390 mg) having the following physical data:

TLC: Rf 0.10 (chloroform: methanol=5:1);

NMR: δ 7.69(1H, d), 7.68(1H, s), 7.05-7.25(2H, m), 6.80-7.00 (2H, m), 6.74 (1H, m), 6.65 (1H, d), 5.73(1H, m), 4.69(1H, dd), 4.51(1H, dd), 4.05 (2H, t), 3.92 (3H, s), 1.87 (2H, m), 1.30-1.55 (4H, m), 0.94 (3H, t);

IR : ν 2940, 2850, 1655, 1600, 1540, 1505, 1450, 1260 cm⁻¹ ;

Mass: m/e 465(M+), 247, 177, 145.

Example 2(1)-2(46)

By the same procedures as reference example 1, 2 and example 1, using a corresponding carboxylic acid and 3-aminopyrocatechol, following compounds having the following physical data, shown in table [XII] were given. ##STR677##

    TABLE XII        Substituent R RF value in TLC     Example in the general (developing        No. formula (Io) solvent) NMR (δppm) IR (νcm.sup.-1) Mass      Appearance               2(1)       ##STR678##       ##STR679##       ##STR680##       ##STR681##       white powder       2(2)      ##STR682##       ##STR683##       ##STR684##       ##STR685##       ##STR686##       ##STR687##       2(3)      ##STR688##       ##STR689##       ##STR690##       ##STR691##       ##STR692##       white powder       2(4)      ##STR693##       ##STR694##       ##STR695##       ##STR696##       ##STR697##       white powder       2(5)      ##STR698##       ##STR699##       ##STR700##       ##STR701##       ##STR702##       ##STR703##       2(6)      ##STR704##       ##STR705##       ##STR706##       ##STR707##       ##STR708##       ##STR709##       2(7)      ##STR710##       ##STR711##       ##STR712##       ##STR713##       ##STR714##       ##STR715##       2(8)      ##STR716##       ##STR717##       ##STR718##       ##STR719##       ##STR720##       ##STR721##       2(9)      ##STR722##       ##STR723##       ##STR724##       ##STR725##       ##STR726##       ##STR727##       2(10)      ##STR728##       ##STR729##       ##STR730##       ##STR731##       ##STR732##       white powder       2(11)      ##STR733##       ##STR734##       ##STR735##       ##STR736##       ##STR737##       ##STR738##       2(12)      ##STR739##       ##STR740##       ##STR741##       ##STR742##       ##STR743##       white powder       2(13)      ##STR744##       ##STR745##       ##STR746##       ##STR747##       ##STR748##       white powder       2(14)      ##STR749##       ##STR750##       ##STR751##       ##STR752##       ##STR753##       white crystal       2(15)      ##STR754##       ##STR755##       ##STR756##       ##STR757##       ##STR758##       white crystal       2(16)      ##STR759##       ##STR760##       ##STR761##       ##STR762##       ##STR763##       white crystal       2(17)      ##STR764##       ##STR765##       ##STR766##       ##STR767##       218, 217       ##STR768##       2(18)      ##STR769##       ##STR770##       ##STR771##       ##STR772##       ##STR773##       ##STR774##       2(19)      ##STR775##       ##STR776##       ##STR777##       ##STR778##       ##STR779##       white powder       2(20)      ##STR780##       ##STR781##       ##STR782##       ##STR783##       ##STR784##       white powder       2(21)      ##STR785##       ##STR786##       ##STR787##       ##STR788##       ##STR789##       white powder       2(22)      ##STR790##       ##STR791##       ##STR792##       ##STR793##       ##STR794##       white powder       2(23)      ##STR795##       ##STR796##       ##STR797##       ##STR798##       ##STR799##       white powder       2(24)      ##STR800##       ##STR801##       ##STR802##       ##STR803##       ##STR804##       white crystal       2(25)      ##STR805##       ##STR806##       ##STR807##       ##STR808##       ##STR809##       white powder       2(26)      ##STR810##       ##STR811##       ##STR812##       ##STR813##       ##STR814##       ##STR815##       2(27)      ##STR816##       ##STR817##       ##STR818##       ##STR819##       ##STR820##       white powder       2(28)      ##STR821##       ##STR822##       ##STR823##       ##STR824##       ##STR825##       white powder       2(29)      ##STR826##       ##STR827##       ##STR828##       ##STR829##       ##STR830##       white powder       2(30)      ##STR831##       ##STR832##       ##STR833##       ##STR834##       ##STR835##       ##STR836##       2(31)      ##STR837##       ##STR838##       ##STR839##       ##STR840##       ##STR841##       white powder       2(32)      ##STR842##       ##STR843##       ##STR844##       ##STR845##       ##STR846##       white powder       2(33)      ##STR847##       ##STR848##       ##STR849##       ##STR850##       ##STR851##       ##STR852##       2(34)      ##STR853##       ##STR854##       ##STR855##       ##STR856##       ##STR857##       white powder       2(35)      ##STR858##       ##STR859##       ##STR860##       ##STR861##       ##STR862##        white powder       2(36)      ##STR863##       ##STR864##       ##STR865##       ##STR866##       ##STR867##       ##STR868##       2(37)      ##STR869##       ##STR870##       ##STR871##       ##STR872##       ##STR873##       white powder       2(38)      ##STR874##       ##STR875##       ##STR876##       ##STR877##       ##STR878##       white powder       2(39)      ##STR879##       ##STR880##       ##STR881##       ##STR882##       ##STR883##       white powder       2(40)      ##STR884##       ##STR885##       ##STR886##       ##STR887##       ##STR888##       white powder       2(41)      ##STR889##       ##STR890##       ##STR891##       ##STR892##       ##STR893##       white powder       2(42)      ##STR894##       ##STR895##       ##STR896##       ##STR897##       ##STR898##       ##STR899##       2(43)      ##STR900##       ##STR901##       ##STR902##       ##STR903##       ##STR904##       white powder       2(44)      ##STR905##       ##STR906##       ##STR907##       ##STR908##       ##STR909##       ##STR910##       2(45)      ##STR911##       ##STR912##       ##STR913##       ##STR914##       ##STR915##       white powder       2(46)      ##STR916##       ##STR917##       ##STR918##       ##STR919##       ##STR920##       white powder

Example 2(101)-2(107)

By the same procedures as reference example 1, 2 and example 2, using a corresponding carboxylic acid and 3-aminopyrocatechol which have corresponding substituents R² and R³ following compounds having the following physical data shown in table [XIII] were given. ##STR921##

    TABLE XIII        Substituent      Ex- R, R.sup.2, R.sup.3 RF value in TLC ample in the      general (developing    Appear- No. formula (Ip) solvent) NMR (δppm)       IR (νcm.sup.-1) Mass ance               2(101)       ##STR922##       ##STR923##       ##STR924##       ##STR925##       ##STR926##       2(102)      ##STR927##       ##STR928##       ##STR929##       ##STR930##       ##STR931##       ##STR932##       2(103)      ##STR933##       ##STR934##       ##STR935##       ##STR936##       ##STR937##       ##STR938##       2(104)      ##STR939##       ##STR940##       ##STR941##       ##STR942##       ##STR943##       ##STR944##       2(105)      ##STR945##       ##STR946##       ##STR947##       ##STR948##       ##STR949##       ##STR950##       2(106)      ##STR951##       ##STR952##       ##STR953##       ##STR954##       ##STR955##       ##STR956##       2(107)      ##STR957##       ##STR958##       ##STR959##       ##STR960##       ##STR961##       ##STR962##

Example 2(201)-2(204)

By the same procedure as reference example 1, 2 and example 2, using with a corresponding carboxylic acid and 3-aminopyrocatechol which have corresponding substituent R³, following compounds having following physical data were given. ##STR963##

TLC: Rf 0.21 (chloroform: methanol=3:1);

NMR: δ 8.03(1H, d), 7.70(1H, d), 7.48(2H, d), 7.20 (2H, d), 6.71 (1H, d), 6.65 (1H, d), 5.57 (1H, s), 4.70-4.40 (2H, m), 2.62 (2H, t);

IR: ν 3700-3000, 1680, 1625, 1610, 1535, 1470, 1440 cm⁻¹ ;

Mass: m/e 201, 179, 162;

Appearance: white powder. ##STR964## (The substituting position of tetrazolyl was not known.)

TLC: Rf 0.22 (methylene chloride: methanol=5:1);

NMR: δ8.21(1H, d), 7.74 (1H, d), 7.57 (1H, d), 7.49 (2H, d), 7.20 (2H, d), 6.62 (1H, d), 5.74 (1H, dd), 4.89(1H,

dd) 4.54 (1H, dd);

IR: ν 3370, 3200-2300, 1695, 1630, 1610, 1520, 1430, 1270, 1140 cm⁻¹ ;

Mass: m/e 477 (M⁺), 291, 201;

Appearance: white crystal ##STR965##

o less polar compound:

TLC: Rf 0.18 (methylene chloride: methanol=5:1);

NMR (CDCl₃): δ 9.88(1H, s), 7.81(1H, d), 7.45(3H, s), 7.18(2H, s), 6.69(1H, s), 6.64(1H, d), 6.04(1H, s), 5.60(1H, s), 4.50(1H, s), 3.84(3H,

IR: ν 3600-2300, 1695, 1630, 1610, 1515, 1470, 1280 cm⁻¹ ;

Mass: m/e 477(M+), 446 , 291, 201;

Appearance: white crystal.

o more polar compound:

TLC : Rf 0.12 (methylene chloride: methanol=5: 1);

NMR (CDCl₃): δ 9.44 (1H, s), 7.46 (1H, s), 7.25 (1H, s), 7.13(2H, s), 6.88(2H, s), 6.60-6.30(2H, s), 5.20 (1H, s), 4.20-3.60(2H, s), 3.72(3H, s), 0.83 (3H, t);

IR: ν 3600-3000, 1695, 1630-1610, 1520, 1480 , 1280 cm⁻¹ ;

Mass: m/e 477 (M⁺), 446, 291, 201;

Appearance: white crystal.

Example 2 (301)

By the same procedure as example 2, using with 8-(p-pentylcinnamoyl) amino-1,4-benzodioxane-2-acetonitrile (synthesized in reference example 5), following compound having the following physical data was given. ##STR966##

TLC: Rf 0.36 (methylene chloride: methanol=5:1);

NMR: δ 7.88 (1H, d), 7.70 (1H, d), 7.47 (2H, d), 7.20 (2H, d), 6.84 (1H, t), 6.63 (1H, dd), 6.57(1H, d), 3.36(2H, d);

IR: ν 3300, 3200-2300, 1660, 1605, 1530, 1460 cm⁻¹ ;

Mass: m/e 433 (M⁺), 233, 201;

Appearance: dark brown powder.

Example 2(302)-2(303)

By the same procedure as example 2, using with a corresponding nitrile, following compounds having the following physical data were given. ##STR967##

TLC: 0.3 (methylene chloride: methanol=5:1);

IR: ν 1655, 1615, 1600, 1540, 1490 cm⁻¹ ;

Mass: m/e 391(M⁺), 349, 309, 217, 201, 191;

Appearance: pale yellow powder ##STR968##

TLC: 0.22 (chloroform: methanol=9:1);

IR: ν 3300-2300, 2920, 1655, 1620, 1540, 1470, 1350, 1045, 980 cm⁻¹ ;

Mass: m/e 407(M+), 324, 292, 201;

Appearance: pale yellow crystal.

Example 3 Synthesis of 8-(P-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester ##STR969##

Oxalyl chloride (3.4 ml) was added to p-pentylcinnamic acid (327 mg), and the mixture was stirred for 30 min at room temperature. Excess oxyalyl chloride was removed from the mixture under reduced pressure. The residue was dissolved to methylene chloride (5 ml). In an atmosphere of argon, a solution of 8-amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester (420 mg) in a mixture of methylene chloride (5 ml) and triethylamine (0.6 ml) was added slowly. The reaction solution was stirred for 1 hr at room temperature, and then poured into 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively, dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate: hexane=1:3) to give the title compound (140 mg) having the following physical data:

TLC: Rf 0.60 (ethyl acetate: hexane=1:1);

NMR (CDCl₃): δ8.76 (1H, dd), 8.23 (1H, s), 7.72 (1H, dd), 7.65(1H, d), 7.38(2H, d), 7.27(1H, t), 7.07 (2H, d), 7.00 (1H, s), 6.52 (1H, d);

IR: ν 3270, 2930, 1730, 1660, 1630, 1530, 1430, 1290, 1260, 1180, 770 cm⁻¹ ;

Mass: m/e 433 (M⁺), 404, 388, 376, 360, 318, 233, 201, 131;

Appearance: white powder.

Example 4 Synthesis of 8- (p-pentylcinnamoyl) amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ##STR970##

8-(p-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester (132 mg; synthesized in example 3) was dissolved into ethanol (10 ml). To the solution, an aqueous solution (1 ml) of sodium bicarbonate (126 mg) was added. The mixture was refluxed for 15 min. To the reaction solution mixture cooled to room temperature, water (20 ml) and 1N hydrochloric acid (2 ml) were added. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried, and concentrated under reduced pressure. The residue was washed with a mixture of ethyl acetate and hexane (1:1), and dried to give the title compound (62 mg) having the following physical data:

TLC: Rf 0.25 (ethyl acetate: methanol=5:1);

NMR: δ 8.66(1H, dd), 7.86(1H, dd), 7.73(1H, d), 7.53(2H, d), 7.43(1H, t), 7.22(2H, d), 7.15(1H, s), 7.08(1H, d);

IR: ν 3400, 2930, 1635, 1520, 1430, 1360 cm⁻¹ ;

Mass: m/e 405(M+), 361, 201, 181, 169, 131, 69;

Appearance: yellow powder.

Example 4(1)-4(3)

By the same procedure as example 3 and 4, using with a corresponding carboxylic acid and 8-amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester which have corresponding substituent R³ following compounds having the following physical data, shown in table [XIV] were given. ##STR971##

                                      TABLE XIV                                    __________________________________________________________________________     Ex-                              RF value                                      am-                                                                               Substituent R,R.sup.3         in TLC                                        ple                                                                               in the general                (developing     IR       Appear-              No.                                                                               formula (Iq)                  solvent)                                                                              NMR (δppm)                                                                        (νcm.sup.-1)                                                                      Mass                                                                              ance                 __________________________________________________________________________     4(1)                                                                                                             ##STR972##                                                                            ##STR973##                                                                              ##STR974##                                                                           ##STR975##                                                                        ##STR976##          4(2)                                                                               ##STR977##                                                                                                   ##STR978##                                                                            ##STR979##                                                                              ##STR980##                                                                           ##STR981##                                                                        ##STR982##          4(3)                                                                               ##STR983##                                                                                                   ##STR984##                                                                            ##STR985##                                                                              ##STR986##                                                                           ##STR987##                                                                        ##STR988##          __________________________________________________________________________

Example 4(101)-4(104)

By the same procedure as example 3 and 4, using with corresponding carboxylic acid and 8-amino-l,4-benzodioxane-2-carboxylic acid ethyl ester, following compounds having the following physical data, shown in table [XV] were given. ##STR989##

                                      TABLE XV                                     __________________________________________________________________________     Ex-                           Rf value                                         am- Substituent R             in TLC                                           ple in the general            (developing      IR         Appear-              No. formula (Ir)              solvent)                                                                              NMR (67 ppm)                                                                             (νcm.sup.-1)                                                                      Mass ance                 __________________________________________________________________________     4(101)                                                                                                        ##STR990##                                                                            ##STR991##                                                                               ##STR992##                                                                           ##STR993##                                                                          ##STR994##          4(102)                                                                              ##STR995##                                                                                               ##STR996##                                                                            ##STR997##                                                                               ##STR998##                                                                           ##STR999##                                                                          ##STR1000##         4(103)                                                                              ##STR1001##                                                                                              ##STR1002##                                                                           ##STR1003##                                                                              ##STR1004##                                                                          ##STR1005##                                                                         ##STR1006##         4(104)                                                                              ##STR1007##                                                                                              ##STR1008##                                                                           ##STR1009##                                                                              ##STR1010##                                                                          ##STR1011##                                                                         ##STR1012##         __________________________________________________________________________

Example 4(201)-4(208)

By the same procedure as example 4, using with a corresponding carboxylic acid and a corresponding amine, following compounds having the following physical data, shown in table [VI] were given.

    TABLE XVI         Rf value in TLC     Example  (developing    Appear- No. Formula      solvent) NMR (δppm) IR (νcm.sup.-1) Mass ance               4(201)       ##STR1013##       ##STR1014##       ##STR1015##       ##STR1016##       ##STR1017##       ##STR1018##       4(202)      ##STR1019##       ##STR1020##       ##STR1021##       ##STR1022##       ##STR1023##       ##STR1024##       4(203)      ##STR1025##       ##STR1026##       ##STR1027##       ##STR1028##       ##STR1029##       4(204)      ##STR1030##       ##STR1031##       ##STR1032##       ##STR1033##       ##STR1034##       ##STR1035##       4(205)      ##STR1036##       ##STR1037##       ##STR1038##       ##STR1039##       ##STR1040##       ##STR1041##       4(206)      ##STR1042##       ##STR1043##       ##STR1044##       ##STR1045##       ##STR1046##       ##STR1047##       4(207)      ##STR1048##       ##STR1049##       ##STR1050##       ##STR1051##       ##STR1052##       ##STR1053##       4(208)      ##STR1054##       ##STR1055##       ##STR1056##       ##STR1057##       ##STR1058##

Example 4 (301)-4 (320)

By the same procedure as example 4, using with a corresponding carboxylic acid and a corresponding amine, following compounds having the following physical data, shown in table [XVII] were given.

                                      TABLE XVII                                   __________________________________________________________________________     Example                                   Rf value in TLC Appear-              No.  Formula                              (developing solvent)                                                                      Mass ance                 __________________________________________________________________________     4(301)                                                                               ##STR1059##                                                                                                         ##STR1060##                                                                               ##STR1061##                                                                         ##STR1062##         4(302)                                                                               ##STR1063##                                                                                                         ##STR1064##                                                                               ##STR1065##                                                                         ##STR1066##         4(303)                                                                               ##STR1067##                                                                                                         ##STR1068##                                                                               ##STR1069##                                                                         ##STR1070##         4(304)                                                                               ##STR1071##                                                                                                         ##STR1072##                                                                               ##STR1073##                                                                         ##STR1074##         4(305)                                                                               ##STR1075##                                                                                                         ##STR1076##                                                                               ##STR1077##                                                                         ##STR1078##         4(306)                                                                               ##STR1079##                                                                                                         ##STR1080##                                                                               ##STR1081##                                                                         ##STR1082##         4(307)                                                                               ##STR1083##                                                                                                         ##STR1084##                                                                               ##STR1085##                                                                         ##STR1086##         4(308)                                                                               ##STR1087##                                                                                                         ##STR1088##                                                                               ##STR1089##                                                                         ##STR1090##         4(309                                                                                ##STR1091##                                                                                                         ##STR1092##                                                                               ##STR1093##                                                                         ##STR1094##         4(310)                                                                               ##STR1095##                                                                                                         ##STR1096##                                                                               ##STR1097##                                                                         ##STR1098##         4(311)                                                                               ##STR1099##                                                                                                         ##STR1100##                                                                               ##STR1101##                                                                         ##STR1102##         4(312)                                                                               ##STR1103##                                                                                                         ##STR1104##                                                                               ##STR1105##                                                                         ##STR1106##         4(313)                                                                               ##STR1107##                                                                                                         ##STR1108##                                                                               ##STR1109##                                                                         ##STR1110##         4(314)                                                                               ##STR1111##                                                                                                         ##STR1112##                                                                               ##STR1113##                                                                         ##STR1114##         4(315)                                                                               ##STR1115##                                                                                                         ##STR1116##                                                                               ##STR1117##                                                                         ##STR1118##         4(316)                                                                               ##STR1119##                                                                                                         ##STR1120##                                                                               ##STR1121##                                                                         ##STR1122##         4(317)                                                                               ##STR1123##                                                                                                         ##STR1124##                                                                               ##STR1125##                                                                         ##STR1126##         4(318)                                                                               ##STR1127##                                                                                                         ##STR1128##                                                                               ##STR1129##                                                                         ##STR1130##         4(319)                                                                               ##STR1131##                                                                                                         ##STR1132##                                                                               ##STR1133##                                                                         ##STR1134##         4(320)                                                                               ##STR1135##                                                                                                         ##STR1136##                                                                               ##STR1137##                                                                         ##STR1138##         __________________________________________________________________________

Example 5 Synthesis of 8-[p- (4-phenylbutoxy) benzoylamino]-2-(5-tetrazolyl) -2,3-dihydrobenzoxazin ##STR1139##

In an atmosphere of argon, a mixture of 8-[p- (4-phenylbutoxy)benzoylamino]-N-trifluoroacetyl-2,3-dihydrobenzoxazin-2-nitrile (316 ammonium chloride (161 mg) and dimethylformamide (2.5 ml}was stirred for 1 hr at 100° C. After reaction, the reaction solution was poured into a mixture of ice and dil. hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed, dried over magnesium sulphate, and condensed under reduced pressure. The residue was dissolved into ethanol which was saturated with ammonia (50 ml). The solution was stirred for 20 hrs at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform: methanol=3:1) to give the title compound (207 mg) having the following physical data:

TLC: Rf 0.36 (chloroform: methanol=3:1);

IR: ν 3600-2300, 1630, 1600, 1500, 1465, 1250, 1170 cm⁻¹ ;

Mass: m/e 470(M⁺) 376, 358, 253;

Appearance: brown powder.

Example 5(1)-5(10)

By the same procedure as example 5, using with a corresponding nitrile, following compounds having the following physical data, shown in table [XVIII] were given.

    TABLE XVIII       Exam-  Rf value in TLC    Appear- ple No. Formula (developing solvent)      NMR (δppm) IR (νcm.sup.-1) Mass ance               5(1)       ##STR1140##       ##STR1141##       ##STR1142##       ##STR1143##       ##STR1144##       ##STR1145##       5(2)      ##STR1146##       ##STR1147##       ##STR1148##       ##STR1149##       ##STR1150##       ##STR1151##       5(3)      ##STR1152##       ##STR1153##       ##STR1154##       ##STR1155##       ##STR1156##       ##STR1157##       5(4)      ##STR1158##       ##STR1159##       ##STR1160##       ##STR1161##       ##STR1162##       ##STR1163##       5(5)      ##STR1164##       ##STR1165##       ##STR1166##       ##STR1167##       ##STR1168##       ##STR1169##       5(6)      ##STR1170##       ##STR1171##       ##STR1172##       ##STR1173##       ##STR1174##       ##STR1175##       5(7)      ##STR1176##       ##STR1177##       ##STR1178##       ##STR1179##       ##STR1180##       ##STR1181##       5(8)      ##STR1182##       ##STR1183##       ##STR1184##       ##STR1185##       5(9)      ##STR1186##       ##STR1187##       ##STR1188##       ##STR1189##       5(10)      ##STR1190##       ##STR1191##         296, 253       ##STR1192##

Example 6 Synthesis of 4-[2-(p-pentyl-2-methylcinnamoyl)-aminophenoxy]-butanoic acid and ethyl ester thereof. ##STR1193##

A mixture of 2-(p-pentyl-2-methylcinnamoyl)aminophenol (267 mg), 4-bromobutanoic acid ethyl ester (322 mg), potassium carbonate (135 mg) and acetone (2 ml) was refluxed overnight. After cooling, the reaction solution was diluted with ethyl acetate, precipitation was removed by filtration from the solution. The solution was concentrated under reduced pressure to give the title compound (ester) having the following physical data:

TLC: Rf 0.66 (toluene: ethyl acetate=10:1);

Mass: m/e 437(M⁺).

Ester obtained was dissolved into methanol (3.2 ml). To the solution, a 2N aqueous solution of sodium hydroxide (1.64 ml), and the solution was stirred for 1.5 hrs at 40° C. After reaction, the solution was acidified with dil. hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure to give the title compound (acid; 285 mg) having the following physical data:

TLC: Rf 0.60 (methylene chloride: methanol=5:1);

IR: ν 3470, 3200-2300, 1710, 1670, 1620, 1600, 1530, 1450, 750 cm⁻¹ ;

NMR (CDCl₃): δ 8.44(1H, dd), 8.28(1H, s), 7.45(1H, s), 7.30(2H, d), 7.18(1H, dd), 4.11(2H, t);

Mass: m/e 409(M⁺), 215, 187;

Appearance: white powder.

Example 6(1)-6(2)

By the same procedure as Example 6, using a corresponding phenol, following compounds were given. ##STR1194##

TLC: Rf 0.48 (ethyl acetate);

IR: ν 3320, 3200-2300, 1700, 1660, 1630, 1610, 1540 cm⁻¹ ;

NMR (CDCl₃ ): δ 8.40(1H, d), 8.22(1H, s), 7.60 (1H, d), 7.34 (2H, s), 7.04 (2H, d), 6.85(1H, dd), 6.76(1H, d), 6.69(1H, dd);

Mass: m/e 395 (M⁺), 201, 195;

Appearance: white powder. ##STR1195##

TLC: 0.4 (methylene chloride: methanol=5:1);

IR: ν 1655, 1600, 1520, 1445 cm⁻¹ ;

Mass: m/e 445(M⁺), 363, 345, 255, 191, 147;

Appearance: pale yellow powder.

Example 7 Synthesis of 8-[3-(p-pentylphenyl)propionyl]amino-2-(5-tetrazolyl) -1,4-benzodioxane ##STR1196##

8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane (216 mg; synthesized in example 2(1)) and palladium-carbon (50 mg; content 5%) were suspended in a mixed solvent (6 ml) of methanol, ethanol and ethyl acetate (1:1:1). In an atmosphere of hydrogen, the suspension was stirred for 90 min at room temperature. After stirring, the suspension was filtered through celite. The filtrate was condensed under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride: methanol=19:1) to give the title compound (202 mg) having the following physical data:

TLC: Rf 0.54 (methylene chloride: methanol=4:1);

NMR (CDCl₃): δ 7.28 (1H, s), 7.11 (4H, 2d), 6.76 (2H, m), 6.60 ( 1H, dd), 5.68 (1H, t), 4.93 (1H, cid), 3.04 (2H, t), 2.77 (2H, m), 2.56 (2H, t), 1.58 (2H, m), 1.30 (4H, m), 0.88 (3H, t);

IR: ν 3600-2300, 1650, 1615, 1530, 1460, 1260, 1100, 780 cm⁻¹ ;

Mass: m/e 421(M⁺), 219;

Appearance: white crystal.

Example 8 Synthesis of 8-[p- (6-hydroxyhexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane ##STR1197##

A 1N aqueous solution of sodium hydroxide (0.5 ml) was added to a solution of 8-[p-(6-acetyloxyhexyloxy)benzoyl]-amino-2-(5-tetrazolyl)-l,4-benzodioxane (100 mg; synthesized in example 1 (96)) in methanol (0.5 ml) at room temperature. The reaction solution was stirred for 10 min at the same temperature, and then concentrated under reduced pressure. To the residue, dil. hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride: methanol=100:1) to give the title compound (95 mg) having the following physical data:

TLC: Rf 0.23 (methylene chloride: methanol=5:1);

NMR: δ 7.89(2H, d), 7.46(1H, dd), 6.95(2H, d), 6.92(1H, t), 6.76(1H, dd), 4.02(2H, t), 3.60 (2H, t);

IR: ν 3400, 3200-2300, 1630, 1600, 1520, 1500, 1440, 1250 cm⁻¹ ;

Mass: m/e 439(M⁺), 221, 149, 121;

Appearance: white amorphous.

Example 9 Synthesis of 8-[p-[5-(N,N-dimethylamino)pentyloxy]cinnamoyl]amino-1,4-benzodioxane sodium salt ##STR1198##

A 40% aqueous solution of dimethylamine (1 ml) was dropped to a solution of 8-[p-(5-bromopentyloxy)cinnamoyl]aino-1,4-benzodioxane (176 mg; synthesized in example 1 (113)). The solution was stirred for 1 hr at room temperature. Volatile matter was removed with vacuum pump for 1 hr at room temperature, and for 3 hrs at 90° C. The residue was dissolved into methanol (1 ml), to the solution, a 2N aqueous solution of sodium hydroxide (360 μl). The mixture was condensed under reduced pressure. To the residue, small amount of methanol and hexane (4 ml ) were added. The mixture was filtered, and volatile matter was removed from the filtrate with vacuum pump overnight at room temperature and overnight at 80° C. to give the title compound (179 mg) having the following physical data:

TLC: Rf 0.33 (ethyl acetate: acetic acid: water=3:1:1);

NMR: δ 7.87 (2H, d), 7.62 (1H, dd), 6.98 (2H, d), 6.86(1H, t), 6.71(1H, dd), 4.06(2H, t), 2.85 (2H, t), 2.64 (2H, s);

IR: ν 3430, 2930, 1655, 1605, 1505, 1445, 1255 cm⁻¹ ;

Mass: m/e 452 (M⁺), 233;

Appearance: white powder.

Example 10 Synthesis of 8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic acid ##STR1199##

8- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl)-1,4-benzodioxane-7-carboxylic acid methyl ester (332 mg; synthesized in example 2 (107) was dissolved in methanol (1.5 ml). To the solution, a 1N aqueous solution of sodium hydroxide (1.36 ml), and the mixture was stirred for 50 min at room temperature and for 2 hrs at 40° C. After cooling, 1N hydrochloric acid (2 ml) was added to the solution. The mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform: methanol=9:1) to give the title compound (263 mg) having the following physical data:

TLC: Rf 0.15 (chloroform: methanol=4:1);

NMR: δ 8.00 (2H, d), 7.68 (1H, d), 6.98 (2H, d), 6.82 (1H, d), 6.04 (1H, m), 4.56 (2H, m), 4.03 (2H, t), 1.82 (2H, m), 1.31 (10H, m), 0.88 (3H, t);

IR: ν 3600-2300, 1680, 1640, 1600, 1490, 1460, 1250, 1170, 1080, 900, 840, 760 cm⁻¹ ;

Mass: m/e 495 (M⁺), 477, 383, 233;

Appearance: pale brown powder.

Example 11 Synthesis of 8- (p-pentylcinnamoyl) amino-2-(5-tetrazolyl) -6-methyl-1,4-benzodioxane sodium salt ##STR1200## 8 -(p-pentylcinnamoyl) -2 -(5 -tetrazolyl ) -6 -methyl-1,4-benzodioxane (50 mg; synthesized in example 2 (103)) was dissolved in methanol (0.5 ml). To the solution, equivalent molar of a 1N aqueous solution of sodium hydroxide was added. The solution was stirred and then evaporated to dryness to give the title compound (51 rag). Example 11(1)

By the same procedure as example 11, corresponding sodium salts of the compounds synthesized in examples (other than example 11 and esters) were given.

Example 12

8-[p-(3E-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane (0.5 g), cellulose calcium gluconate (200 mg; disintegrator), magnesium stearate (100 mg; lubricator) and microcrystalline cellulose (9.2 g) were admixed and punched out in conventional manner to give 100 tablets each containing 5 mg of the active ingredient. 

What is claimed is:
 1. A novel (fused) benz(thio)amide of the general formula: ##STR1201## or a non-toxic salt thereof, wherein A represents a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethylene group optionally being substituted by one, two or three groups selected from the group consisting of straight or branched alkyl groups having from 1 to 10 carbon atoms and phenyl groups;B represents:(i) a carboxylic ring of from 4 to 8 members optionally substituted by at least one group selected from the group consisting of oxo, thioxo and hydroxy groups; or (ii) a divalent group of the formula: ##STR1202## T represents an oxygen atom or a sulphur atom; R¹ represents a group of the general formula: ##STR1203## (iv) a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s), wherein R⁵ and R⁶ independently represent a hydrogen atom; a halogen atom; or a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s) being unreplaced or having one, two, three, four or five optional carbon atom(s) replaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) or nitro group(s); R² represents a hydrogen atom; R³ represents a hydrogen atom; R⁴ represents:(i) when B represents a closed ring, a group of the general formula: ##STR1204## wherein U represents an oxygen atom or a sulphur atom; R⁸ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); n and m independently represent an integer of from 1 to 10, and p and q independently represent zero or an integer of from 1 to 10; or (ii) when B does not represent a ring, a group of the general formula: ##STR1205## wherein R⁸, p and q each has the same meaning as defined above; with the following provisos (A) and (B): (A) when B represents a group of the formula: ##STR1206## °p does not represent zero; and (B) compounds of the general formula (I') and non-toxic salts thereof are excluded: ##STR1207## wherein A' has the same definition as A in general formula (I) above; R^(4') represents:

    --(CH.sub.2).sub.p --COOR.sup.8

wherein R⁸ and p each has the same meaning as defined above; and R^(1') represents:(i) a group of the general formula: ##STR1208## wherein R^(5') and R^(6') have the same definition as R⁵ and R⁶ above; or (ii) a group of the general formula: ##STR1209## wherein R^(5') and R^(6') have the same meaning as defined above.
 2. A compound according to claim 1, wherein B represents a closed ring, and said compound is represented by the general formula: ##STR1210## wherein R¹, A, T, R², R³ and R⁴ each has the same meaning as in claim
 1. 3. A compound according to claim 2, wherein B represents a benzene ring.
 4. A compound according to claim 3, wherein A represents a vinylene group being unsubstituted or substituted by at least one group selected from the group consisting of a straight or branched alkyl group having from 1 to 6 carbon atoms and a phenyl group; and T represents an oxygen atom.
 5. A compound according to claim 4, wherein R¹ represents a group of the general formula: ##STR1211## wherein R⁵ and R⁶ each has the same meaning as defined in claim
 1. 6. A compound according to claim 1, wherein B represents said divalent group of the formula ##STR1212##
 7. A compound according to claim 6, wherein B represents said divalent group of the formula ##STR1213##
 8. A compound according to claim 7, wherein A represents a vinylene group being unsubstituted or substituted by at least one group selected from the group consisting of a straight or branched alkyl group having from 1 to 6 carbon atoms and a phenyl group; and T represents an oxygen atom.
 9. A compound according to claim 8, wherein R¹ represents a group of the general formula: ##STR1214## wherein R⁵ and R⁶ each has the same meaning as defined in claim
 1. 10. A compound according to claim 9, which is selected from the group consisting of:N-(P-pentylcinnamoyl)-2-(5-tetrazolyl)methoxyanilide, N-[p-(2-octynyl)cinnamoyl]-2-(5-tetrazolyl)methoxyanilide, and sodium salts thereof.
 11. A compound according to claim 6, wherein B represents said divalent group of the formula ##STR1215##
 12. A compound according to claim 11, wherein A represents a vinylene group being unsubstituted or substituted by at least one group selected from the group consisting of a straight or branched alkyl group having from 1 to 6 carbon atoms and a phenyl group; and T represents an oxygen atom.
 13. A compound according to claim 12, wherein R¹ represents a group of the general formula: ##STR1216## wherein R⁵ and R⁶ each has the same meaning as defined in claim
 1. 14. A compound according to claim 13, which is selected from the group consisting of:4-[2-(p-pentyl-2-methylcinnamoyl)aminophenylthio]butanoic acid, 4-[2-(p-pentyl-3-methylcinnamoyl)aminophenylthio]butanoic acid, 4-[2-(p-pentylcinnamoyl)aminophenylthio]butanoic acid, N-(p-pentylcinnamoyl)-2-(5-tetrazolyl)methylthioanilide, 3-[2-(p-pentylcinnamoyl)aminophenylthio]propionic acid, 4-[2-(p-isopropylcinnamoyl)aminophenylthio]butanoic acid, 4-[2-(p-cyclohexylcinnamoyl)aminophenylthio]butanoic acid, 4-[2-(p-phenylmethylcinnamoyl)aminophenylthio]butanoic acid, 4-[2-[p-(2-octynyloxy)cinnamoyl]aminophenylthio]butanoicacid and sodium salts thereof.
 15. A pharmaceutical composition comprising, as active ingredient, at least one pharmaceutically active compound of general formula (I) as defined in claim 1 or a non-toxic salt thereof, together with at least one of a pharmaceutical carrier and a coating.
 16. A novel (fused) benz (thio) amide of the general formula: ##STR1217## or a non-toxic salt thereof, wherein A represents a single bond;B represents a carbocyclic ring of from 4 to 8 members optionally substituted by at least one group selected from the group consisting of oxo, thioxo and hydroxy groups T represents an oxygen atom or a sulphur atom; R¹ represents a group of the general formula: ##STR1218## (iv) a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s),wherein R⁵ and R⁶ independently represent a hydrogen atom; a halogen atom; or a straight or branched alkyl, alkenyl or alkynyl group having from 1 to 20 carbon atoms being unreplaced or having one, two, three, four or five optional carbon atom(s) replaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) or nitro group(s); R² represents a hydrogen atom; R³ represents a hydrogen atom; R⁴ represents a group of the general formula: ##STR1219## wherein U represents an oxygen atom or a sulphur atom; R⁸ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s);n and m independently represent an integer of from 1 to 10; and p and q independently represent zero or an integer of from 1 to
 10. 17. A compound according to claim 16, wherein B represents a benzene ring.
 18. A compound according to claim 17, wherein T represents an oxygen atom.
 19. A compound according to claim 18, wherein R¹ represents a group of the general formula: ##STR1220## wherein R⁵ and R⁶ each has the same meaning as defined in claim
 16. 20. A compound according to claim 19, which is selected from the group consisting of:8-[P-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)naphthalene, 8-[P-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)naphthalene, 8-[P-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)methoxynaphthalene, 8-[p-(2-phenylethoxy)benzoyl]amino-2-(5-tetrazolyl)methoxynaphthalene, 8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)methoxynaphthalene,and sodium salts thereof.
 21. A novel (fused) benz(thio)amide of the general formula: ##STR1221## or a non-toxic salt thereof, wherein A represents a single bond; p1 B represents a divalent group of the formula: ##STR1222## T represents an oxygen atom or a sulphur atom; R¹ represents a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s);R² represents a hydrogen atom; R³ represents a hydrogen atom; R⁴ represents a group of the general formula: ##STR1223## wherein R⁸ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); p represents an integer of from 1 to 10; and q represents zero or an integer of from 1 to
 10. 22. A method for the prevention of diseases which are induced by leukotrienes or for the treatment of diseases which are induced by leukotrienes, comprising administering a therapeutically effective amount of a fused benz(thio)amide of the general formula: ##STR1224## or a non-toxic salt thereof, wherein A represents a single bond or a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethylene group optionally being substituted by one, two or three groups selected from the group consisting of straight or branched alkyl groups having from 1 to 10 carbon atoms and phenyl groups;B represents:(i) a carbocyclic ring of from 4 to 8 members being unreplaced or having one, two or three carbon atom(s) optionally replaced by oxygen, nitrogen or sulphur atom(s), said ring being optionally substituted by at least one group selected from the group consisting of oxo, thioxo and hydroxy groups; T represents an oxygen atom or a sulphur atom; R¹ represents a group of the general formula: ##STR1225## (iv) a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s), wherein R⁵ and R⁶ independently represent a hydrogen atom; a halogen atom; or a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s) being unreplaced or having one, two, three, four or five carbon atom(s) optionally replaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) or nitro group(s); R² represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); R³ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a straight or branched alkyl, alkoxy or alkylthio group of from 1 to 6 carbon atom(s), or a group of general formula --COOR⁷ wherein R⁷ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atoms(s); R⁴ represents a group of the general formula: ##STR1226## wherein U represents an oxygen atom or a sulphur atom; R⁸ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); n and m independently represent an integer of from 1 to 10, and p and q independently represent zero or an integer of from 1 to
 10. 23. The method according to claim 22, wherein B represents a ring selected from the following formulae: ##STR1227## said ring represented by B being unsubstituted or further substituted by at least one hydroxy group.
 24. A method for the prevention of diseases which are induced by 5α-reductase, or for the treatment of diseases which are induced by 5α-reductase, comprising administering a therapeutically effective amount of a compound of the general formula: ##STR1228## or a non-toxic salt thereof, wherein A represents a single bond or a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethylene group optionally being substituted by one, two or three groups selected from the group consisting of straight or branched alkyl groups having from 1 to 10 carbon atoms and phenyl groups;B represents:(i) a carbocyclic ring of from 4 to 8 members being unreplaced or having one, two or three carbon atom(s) optionally replaced by oxygen, nitrogen or sulphur atom(s), said ring being optionally substituted by at least one group selected from the group consisting of oxo, thioxo and hydroxy groups; T represents an oxygen atom or a sulphur atom; R¹ represents a group of the general formula: ##STR1229## (iv) a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s), wherein R⁵ and R⁶ independently represent a hydrogen atom; a halogen atom; or a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s) being unreplaced or having one, two, three, four or five carbon atom(s) optionally replaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) or nitro group(s); R² represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); R³ represent s a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a straight or branched alkyl, alkoxy or alkylthio group of from 1 to 6 carbon atom(s), or a group of general formula --COOR⁷ wherein R⁷ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atoms(s); R⁴ represents a group of the general formula: ##STR1230## wherein U represents an oxygen atom or a sulphur atom; R⁸ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); n and m independently represent an integer of from 1 to 10, and p and q independently represent zero or an integer of from 1 to
 10. 25. The method according to claim 24, wherein B represents a ring selected from the following formulae: ##STR1231## said ring represented by; B being unsubstituted or further substituted by at least one hydroxy group.
 26. A novel (fused) benz(thio)amide of the general formula: ##STR1232## or a non-toxic salt thereof, wherein A represents a single bond;B represents a carbocyclic ring of 4 members optionally substituted by at least one group selected from the group consisting of oxo, thioxo and hydroxy groups; T represents an oxygen atom or a sulphur atom; R¹ represents a group of the general formula: ##STR1233## (iv) a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s),wherein R⁵ and R⁶ independently represent a hydrogen atom; a halogen atom; or a straight or branched alkyl, alkenyl or alkynyl group having from 1 to 20 carbon atoms being unreplaced or having one, two, three, four or five optional carbon atom(s) replaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) or nitro group(s); R² represents a hydrogen atom; R³ represents a hydrogen atom; R⁴ represents a group of the general formula: ##STR1234## wherein U represents an oxygen atom or a sulphur atom; R⁸ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s);n and m independently represent an integer of from 1 to 10; and p and q independently represent zero or an integer of from 1 to
 10. 27. A compound according to claim 26, wherein T represents an oxygen atom.
 28. A compound according to claim 26, wherein R¹ represents a group of the general formula: ##STR1235## wherein R⁵ and R⁶ each has the same meaning as defined in claim
 26. 29. A method for the prevention of diseases which are induced by leukotrienes or for the treatment of diseases which are induced by leukotrienes, comprising administering a therapeutically effective amount of a fused benz(thio)amide of the general formula: ##STR1236## or a non-toxic salt thereof, wherein: A represents a single bond;B represents a carbocyclic ring of 4 members optionally substituted by at least one group selected from the group consisting of oxo, thioxo and hydroxy groups; T represents an oxygen atom or a sulphur atom; R¹ represents a group of the general formula: ##STR1237## (iv) a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s), wherein R^(s) and R^(s) independently represent a hydrogen atom; a halogen atom; or a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s) being unreplaced or having one, two, three, four or five carbon atom(s) optionally replaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) or nitro group(s); R² represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); R³ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a straight or branched alkyl, alkoxy or alkylthio group of from 1 to 6 carbon atom(s), or a group of general formula --COOR⁷ wherein R⁷ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atoms(s); R⁴ represents a group of the general formula: ##STR1238## wherein U represents an oxygen atom or a sulphur atom; R⁸ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); n and m independently represent an integer of from 1 to 10, and p and q independently represent zero or an integer of from 1 to
 10. 30. A method for the prevention of diseases which are induced by 5α-reductase, or for the treatment of diseases which are induced by 5α-reductase, comprising administering a therapeutically effective amount of a compound of the general formula: ##STR1239## or a non-toxic salt thereof, wherein: A represents a single bond;B represents a carbocyclic ring of 4 members optionally substituted by at least one group selected from the group consisting of oxo, thioxo and hydroxy groups; T represents an oxygen atom or a sulphur atom; R¹ represents a group of the general formula: ##STR1240## (iv) a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s), wherein R⁵ and R⁶ independently represent a hydrogen atom; a halogen atom; or a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s) being unreplaced or having one, two, three, four or five carbon atom(s) optionally replaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) or nitro group(s); R² represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); R³ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a straight or branched alkyl, alkoxy or alkylthio group of from 1 to 6 carbon atom(s), or a group of general formula --COOR⁷ wherein R⁷ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atoms(s); R⁴ represents a group of the general formula: ##STR1241## wherein U represents an oxygen atom or a sulphur atom; R⁸ represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s); n and m independently represent an integer of from 1 to 10, and p and q independently represent zero or an integer of from 1 to
 10. 